Amine compounds and use thereof

ABSTRACT

Novel amine compounds which are efficacious against diseases such as infection with HIV virus, rheumatism, and cancer metastasis include compounds represented by the following general formula (1), a pharmacologically acceptable salt thereof, or a prodrug thereof: 
                         
wherein each of n 1 , n 2 , and n 3  is an integer of 1; each of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6  is independently a hydrogen atom; A 1  is imidazole; A 2  is imidazole or imidazole substituted with an alkyl group; W is a phenyl group or naphthyl group; X is CH 2 ; D is a group represented by -Q-Y—B, wherein Q is NR 12  and R 12  is a hydrogen atom or an alkyl group; Y is (CH 2 )m 3  and m 3  is an integer of 2 to 4; and B is N(R 25 R 26 ), wherein each of R 25  and R 26  are independently a hydrogen atom, a C 1 –C 6  alkyl group or a C 3 –C 6  cycloalkyl group.

This application is a 371 U.S. national stage application ofinternational application PCT/JP2003/011381 filed Sep. 5, 2003, whichclaims priority of Japanese patent application 265247/2002 filed Sep.11, 2002.

TECHNICAL FIELD

The present invention relates to an amine compound or apharmacologically acceptable salt thereof, or a prodrug thereof, inparticular, an amine compound having anti-virus activity based onantagonism to chemokine receptor CXCR4. Furthermore, the presentinvention relates to a pharmaceutical drug for associated diseases suchas rheumatic diseases and cancer metastatic diseases, based onantagonism against a chemokine receptor CXCR4.

BACKGROUND ART

While examples of therapeutic drugs against the acquiredimmunodeficiency syndrome (AIDS) caused by an infection with the humanimmunodeficiency virus (HIV) include a reverse transcriptase inhibitorand a protease inhibitor, therapeutic effectiveness of those drugs hasbeen lost due to the emergence of drug resistant HIV mutants (see, forexample, Saishin Igaku, Vol. 53, No. 9, p. 2031 (1998)). Also, thepolypharmacy using the combination of such drugs has such disadvantagesthat it requires many conditions to be observed in administration, thatit is complex, that it needs many kinds of drugs to be administered, andthat it causes various side effects (see, for example, Nikkei Science,October, p. 29 (1998)). Moreover, particularly in case of using theprotease inhibitor, it is known that the probability of causingemergence and screening of the resistant strain will increase unless theadministration of approximately 100% of the drugs is kept, in spite ofthe complex administration method and many side effects thereof (see,for example, Molecular Medicine, Vol. 36, No. 9, p. 1012 (1999)).

Alternatively, development of vaccine has been attempted because manyviral diseases were destroyed or remarkably weakened by vaccines in thepast. However, this is considered to be extremely difficult sincemutations are occurred frequently in HIV (see, for example, NikkeiScience, October, p. 42 (1998)).

Although several kinds of compounds having an anti-HIV effect have beenreported as described above, it is now strongly desired to develop anovel antiviral drug which has excellent anti-retrovirus effect, iscapable of opposing to the expression of the resistance, and which haslittle toxicity and causes little side effect, thereby allowing longterm administration.

Chemokines is one kind of cytokine which renders chemotaxis toleukocytes, and is a secretory protein. Chemokine is classified intoCXC-chemokine, CC-chemokine, C-chemokine, CX3C-chemokine according tothe cysteine (Cys) sequence at N-terminal, and the total number thereofis said to be about 30. The chemokine receptor includes several subtypes. Among them, it is known that the CXCR4 which is a ligand forCXC-chemokine SDF-1 is utilized as a coreceptor on infection to a hostcell of T cell-directive HIV (see, for example, Science, 272, 872 (1996)and Nature, 382, 829 (1996). The HIV invades through binding to theCXCR4 on the surface of a host cell of an envelope protein gp120. Thatis, the drug having antagonism against the CXCR4 is expected as ananti-HIV drug based on a novel mechanism of invasion inhibition, andthere have been reported three low molecular compounds as such drugs:AMD3100 (see, for example, J. Exp. Med, 186, 1383 (1997), T22 (see, forexample, J. Exp. Med, 186, 1389 (1997)), and ALX40-4C (see, for example,J. Exp. Med, 186, 1395 (1997)).

On the other hand, it has been elucidated that the CXCR4 associates withvarious diseases besides HIV infection. For example, there has beenreported its association with rheumatic disease (see, for example, WO00/06086), cancer metastatic disease (see, for example, Nature, 410, 50(2001)), etc.

As a therapeutic drug for such diseases, it is strongly desired todevelop a novel low-molecular drug which has CXCR4 antagonism, and whichhas little toxicity and causes little side effect, thereby allowinglong-term administration.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a drug and a prodrugthereof having an excellent anti-retrovirus effect, and also a novelchemical structure having an excellent CXCR4 antagonism against SDF-1,and high safety.

As a result of studies to develop a compound having an excellentanti-retrovirus effect, and also having a novel chemical structureuseful as an excellent CXCR4 antagonist against SDF-1, the presentinventors have found a group of amine compounds which exhibit protectioncharacteristics in a cell vaccinated with HIV-1 and therefore areregarded as having a potentiality for treatments of AIDS,AIDS-associated complication, and the like, and which also exhibit apowerful CXCR4 antagonism and therefore are regarded as having apotentiality for treatments of rheumatic disease, cancer metastaticdiseases, and the like. Thus, another object of the present invention isto provide a compound represented by the general formula (1) definedbelow, which has an anti-virus activity for mainly HIV and a CXCR4antagonism, and still another object of the invention is to provide adrug comprising the compound represented by the general formula (1), fortreating virus-infected patients and patients suffering from rheumatism,cancer, or the like.

That is, the present invention relates to a compound represented by thefollowing general formula (1), a pharmacologically acceptable saltthereof, or a prodrug thereof:

wherein

each of n₁, n₂, and n₃ is an integer of 0 to 3;

each of R₁, R₂, R₃, R₄, R₅, and R₆ is independently a hydrogen atom, asubstitutable alkyl group having 1 to 15 carbon atoms, preferably 1 to10 carbon atoms, and more preferably 1 to 7 carbon atoms, asubstitutable alkenyl group having 2 to 15 carbon atoms, preferably 2 to10 carbon atoms, and more preferably 2 to 7 carbon atoms, asubstitutable alkynyl group having 2 to 15 carbon atoms, preferably 2 to10 carbon atoms, and more preferably 2 to 7 carbon atoms, or asubstitutable cyclic alkyl group having 3 to 15 carbon atoms, preferably3 to 10 carbon atoms, and more preferably 3 to 7 carbon atoms; and

each of A₁ and A₂ is independently a substitutable monocyclic orpolycyclic heteroaromatic ring, a partly saturated substitutablepolycyclic heteroaromatic ring, a substitutable monocyclic or polycyclicaromatic ring, a partly saturated substitutable polycyclic aromaticring, a substitutable heterocycle, or a group represented by thefollowing formula (2):

wherein

each of R₇, R₈, R₉, and R₁₀ is independently a hydrogen atom, asubstitutable alkyl group having 1 to 15 carbon atoms, preferably 1 to10 carbon atoms, and more preferably 1 to 7 carbon atoms, asubstitutable alkenyl group having 2 to 15 carbon atoms, preferably 2 to10 carbon atoms, and more preferably 2 to 7 carbon atoms, asubstitutable alkynyl group having 2 to 15 carbon atoms, preferably 2 to10 carbon atoms, and more preferably 2 to 7 carbon atoms, or asubstitutable cyclic alkyl group having 3 to 15 carbon atoms, preferably3 to 10 carbon atoms, and more preferably 3 to 7 carbon atoms;

W is a substitutable alkylene group having 1 to 15 carbon atoms,preferably 1 to 10 carbon atoms, and more preferably 1 to 7 carbonatoms, a substitutable alkenylene group having 2 to 15 carbon atoms,preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbonatoms, a substitutable alkynylene group having 2 to 15 carbon atoms,preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbonatoms, a substitutable cyclic alkylene group having 3 to 15 carbonatoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 7carbon atoms, a substitutable monocyclic or polycyclic heteroaromaticring, a partly saturated substitutable polycyclic heteroaromatic ring, asubstitutable monocyclic or polycyclic aromatic ring, a partly saturatedsubstitutable polycyclic aromatic ring, or a substitutable heterocycle;

X is O, CH₂, NR₁₁, or a group represented by the following formula (3);

R₁₁ is a hydrogen atom, a substitutable alkyl group having 1 to 15carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to7 carbon atoms, a substitutable alkenyl group having 2 to 15 carbonatoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7carbon atoms, a substitutable alkynyl group having 2 to 15 carbon atoms,preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbonatoms, or a substitutable cyclic alkyl group having 3 to 15 carbonatoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 7carbon atoms;

wherein

m₁ is an integer of 1 or 2;

D is a group represented by the following formula (4) or (6):

wherein

R₁₃ is a hydrogen atom, a substitutable alkyl group having 1 to 15carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to7 carbon atoms, a substitutable alkenyl group having 2 to 15 carbonatoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7carbon atoms, a substitutable alkynyl group having 2 to 15 carbon atoms,preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbonatoms, or a substitutable cyclic alkyl group having 3 to 15 carbonatoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 7carbon atoms, or a group represented by the following formula (5):

wherein

m₂ is an integer of 2 to 4;

each of R₁₄, R₁₅, R₁₆, and R₁₇ is independently a hydrogen atom, asubstitutable alkyl group having 1 to 15 carbon atoms, preferably 1 to10 carbon atoms, and more preferably 1 to 7 carbon atoms, asubstitutable alkenyl group having 2 to 15 carbon atoms, preferably 2 to10 carbon atoms, and more preferably 2 to 7 carbon atoms, asubstitutable alkynyl group having 2 to 15 carbon atoms, preferably 2 to10 carbon atoms, and more preferably 2 to 7 carbon atoms, or asubstitutable cyclic alkyl group having 3 to 15 carbon atoms, preferably3 to 10 carbon atoms, and more preferably 3 to 7 carbon atoms;

wherein

Q is a single bond when X is O, a single bond or a group represented bythe formula (3) when X is NR₁₁, or a single bond, S, O, or NR₁₂ when Xis CH₂ or represented by the formula (3);

R₁₂ is a hydrogen atom, a substitutable alkyl group having 1 to 15carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to7 carbon atoms, a substitutable alkenyl group having 2 to 15 carbonatoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7carbon atoms, a substitutable alkynyl group having 2 to 15 carbon atoms,preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbonatoms, or a substitutable cyclic alkyl group having 3 to 15 carbonatoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 7carbon atoms; and

Y is a group represented by the following formula (7):

wherein

m₃ is an integer of 0 to 6;

each of R₁₈ and R₁₉ is independently a hydrogen atom, a substitutablealkyl group having 1 to 15 carbon atoms, preferably 1 to 10 carbonatoms, and more preferably 1 to 7 carbon atoms, a substitutable alkenylgroup having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, andmore preferably 2 to 7 carbon atoms, a substitutable alkynyl grouphaving 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and morepreferably 2 to 7 carbon atoms, a substitutable cyclic alkyl grouphaving 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, and morepreferably 3 to 7 carbon atoms, or a substitutable aromatic ring, andR₁₂ and R₁₈ may form a ring;

each of m₄ and m₅ is an integer of 0 to 2;

each of R₂₀, R₂₁, R₂₂, and R₂₃ is independently a hydrogen atom, asubstitutable alkyl group having 1 to 15 carbon atoms, preferably 1 to10 carbon atoms, and more preferably 1 to 7 carbon atoms, asubstitutable alkenyl group having 2 to 15 carbon atoms, preferably 2 to10 carbon atoms, and more preferably 2 to 7 carbon atoms, asubstitutable alkynyl group having 2 to 15 carbon atoms, preferably 2 to10 carbon atoms, and more preferably 2 to 7 carbon atoms, or asubstitutable cyclic alkyl group having 3 to 15 carbon atoms, preferably3 to 10 carbon atoms, and more preferably 3 to 7 carbon atoms;

z is a substitutable cyclic alkylene group having 3 to 15 carbon atoms,preferably 3 to 10 carbon atoms, and more preferably 3 to 7 carbonatoms, a substitutable monocyclic or polycyclic heteroaromatic ring, apartly saturated substitutable polycyclic heteroaromatic ring, asubstitutable monocyclic or polycyclic aromatic ring, a partly saturatedsubstitutable polycyclic aromatic ring, or a substitutable heterocycle;

B is a group represented by the following formula (8):

wherein

Q₁ is S, O, or NH and Q₂ is S, O, or NR₂₇;

each of R₂₄ and R₂₇ is independently a hydrogen atom, a substitutablealkyl group having 1 to 15 carbon atoms, preferably 1 to 10 carbonatoms, and more preferably 1 to 7 carbon atoms, a substitutable alkenylgroup having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, andmore preferably 2 to 7 carbon atoms, a substitutable alkynyl grouphaving 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and morepreferably 2 to 7 carbon atoms, a substitutable cyclic alkyl grouphaving 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, and morepreferably 3 to 7 carbon atoms, or a substitutable aromatic ring, andR₂₄ and R₂₇ may form a ring;

each of R₂₅ and R₂₆ is, when above X is CH₂, independently a hydrogenatom, a substitutable alkyl group having 1 to 15 carbon atoms,preferably 1 to 10 carbon atoms, and more preferably 1 to 7 carbonatoms, a substitutable cyclic alkyl group having 3 to 15 carbon atoms,preferably 3 to 10 carbon atoms, and more preferably 3 to 7 carbonatoms, a substitutable alkenyl group having 2 to 15 carbon atoms,preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atomsand 1 to 3 double bonds, or a substitutable alkynyl group having 2 to 15carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to7 carbon atoms and having 1 to 3 triple bonds, where R₂₅ and R₂₆ mayform a ring and, depending on circumstances, the ring may be formed bybinding through a heteroatom, a cyclic alkyl group, an aromatic ring, aheteroaromatic ring, or a heterocycle;

each of R₂₅ and R₂₆ is, when above X is not CH₂, independently ahydrogen atom, a substituent represented by the following formula (9), asubstitutable alkyl group having 1 to 15 carbon atoms, preferably 1 to10 carbon atoms, and more preferably 1 to 7 carbon atoms, asubstitutable cyclic alkyl group having 3 to 15 carbon atoms, preferably3 to 10 carbon atoms, and more preferably 3 to 7 carbon atoms, asubstitutable alkenyl group having 1 to 3 double bonds and 2 to 15carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to7 carbon atoms, or a substitutable alkynyl group having 1 to 3 triplebonds and 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, andmore preferably 2 to 7 carbon atoms, and R₂₅ and R₂₆ may form a ringand, depending on circumstances, the ring may be formed by bindingthrough a heteroatom, a cyclic alkyl group, an aromatic ring, aheteroaromatic ring, or a heterocycle:

wherein

m₆ is 0 or 1, where when m₆=0, Q₃ is CH or N and Q₄ is N, S, or O, andwhen m₆=1, each of Q₃ and Q₄ is independently CH or N;

G is a substitutable alkylene group having 1 to 15 carbon atoms,preferably 1 to 10 carbon atoms, and more preferably 1 to 7 carbon atomsor a substitutable alkenylene group having 2 to 15 carbon atoms,preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbonatoms;

R₂₈ is an alkyl group having 1 to 15 carbon atoms, preferably 1 to 10carbon atoms, and more preferably 1 to 7 carbon atoms to be substitutedat any position except a nitrogen atom which may be present on the ring,a substitutable alkenyl group having 2 to 15 carbon atoms, preferably 2to 10 carbon atoms, and more preferably 2 to 7 carbon atoms, asubstitutable alkynyl group, alkoxy group, a haloalkyl group, ahaloalkoxy group, a hydroxyalkoxy group, a halogen atom, an amino group,an alkylamino group, a carboxyl group, an alkoxycarbonyl group, acarbamoyl group, an alkylcarbamoyl group, a saturated heterocycle, or aheteroaromatic ring having 2 to 15 carbon atoms, preferably 2 to 10carbon atoms, and more preferably 2 to 7 carbon atoms, or may be ahydrogen atom when m₆=1 and Q₃ and Q₄ are both CH; and

R₂₉ is a hydrogen atom or the same group as R₂₄, which may be coupledwith G to form a ring.

one or two or more asymmetric carbon atoms may exist in the compoundrepresented by the general formula (1), where when one asymmetric carbonatom exists, the compound may be in the form of any one of a pureoptically active substance represented by the absolute configuration Ror S, a mixture thereof in a predetermined ratio, and a racemic mixturethereof or when two or more asymmetric carbon atoms exist, the compoundmay be in the form of any one of an optically pure diastereomer, aracemic mixture thereof, and a combination thereof in a predeterminedratio.

The terms as used in this specification are defined as described below,and they may be used singly or in combination.

An alkyl group represents a saturated hydrocarbon group with anystructure of a linear chain, a branched chain, or a ring. Examples ofthe alkyl group include a methyl group, an ethyl group, an n-propylgroup, an isopropyl group, an n-butyl group, an isobutyl group, a pentylgroup, and a neopentyl group.

An alkenyl group represents a hydrocarbon group with any structure of alinear chain, a branched chain, or a ring having a double bond. Examplesof the alkenyl group include an allyl group, a 1-butenyl group, a2-butenyl group, an isobutenyl group, and a cyclohexenyl group.

An alkynyl group represents a hydrocarbon group with any structure of alinear chain, a branched chain, or a ring having a triple bond. Examplesof the alkynyl group include a propynyl group and a 1-butynyl group.

A cyclic alkyl group represents a cyclic hydrocarbon group. Examples ofthe cyclic alkyl group include a cyclopropyl group, a cyclobutyl group,a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.

An aromatic ring represents an aromatic ring formed of a hydrocarbon.Examples of a monocyclic aromatic ring include a benzene ring; andexamples of a polycyclic aromatic ring include a naphthalene ring and ananthracene ring. Examples of a partly saturated polycyclic aromatic ringinclude a dihydronaphthalene ring, a tetralin ring, an indan ring andthe like. A heteroaromatic ring represents an aromatic ring having oneor two or more nitrogen atoms, oxygen atoms, or sulfur atoms in thering. Examples of a monocyclic heteroaromatic ring include a pyrrolering, a furan ring, a thiophene ring, a pyridine ring, a pyrimidinering, a pyridazine ring, a pyrazine ring, an imidazole ring, a pyrazolering, an oxazole ring, a thiazole ring, a thiadiazole ring, anoxadiazole ring, and a triazole ring. Examples of a polycyclicheteroaromatic ring include a quinoline ring, an isoquinoline ring, abenzimidazole ring, an indazole ring, a benzothiazole ring, abenzoxazole ring, an indole ring, a benzofuran ring, and abenzothiophene ring.

Examples of a partly saturated polycyclic aromatic ring include atetrahydroisoquinoline ring and a tetrahydroquinoline ring. Aheterocycle represents a saturated ring that may have one or two or morenitrogen atoms, oxygen atoms, or sulfur atoms in the ring. Examples ofthe heterocycle include pyrrolidine, piperidine, piperazine, morpholine,and thiomorpholine.

An alkylene group represents a hydrocarbon group that can be bonded twogroups at the terminals. Examples of the alkylene group include anethylene group, a propylene group, an isopropylene group, a butylenegroup, an isobutylene group, and a 2,2-dimethylethylene group.

An alkenylene group represents an alkylene group having a double bond.Examples of the alkenylene group include a propenylene group, a2-butenylene group, and a 1,3-butadienylene group.

An alkynylene group represents an alkylene group having a triple bond.Examples of the alkynylene group include a propynylene group and abutynylene group.

The cyclic alkylene group in W represents a cyclic hydrocarbon groupthat can be bonded two groups at any positions. Examples of the cyclicalkylene group include a cyclopropylene group, a cyclopentylene group, acyclohexylene group, and a tetralinylene group. An aromatic ring alsorepresents an aromatic ring that can be bonded two groups at anypositions. Examples of the aromatic ring group include a phenylene groupand a napthalene group.

A heteroaromatic ring also represents a heteroaromatic ring that can bebonded two groups at any positions. Examples of the heteroaromatic ringto be used include a pyrrole ring, a furan ring, a thiophene ring, apyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, animidazole ring, a thiazole ring, an oxazole ring, a triazole ring, aquinoline ring, an isoquinoline ring, a benzimidazole ring, abenzothiazole ring, a benzoxazole ring, an indole ring, a benzofuranring, and a benzothiophene ring.

B represents R₂₅(R₂₆)N—, where R₂₅ and R₂₆ may form a ring. Examples ofa ring formed by binding R₂₅ and R₂₆ directly together with a nitrogenatom to which they are bound include a pyrrolidine ring, a piperidinering, a hexamethyleneimine ring, and a heptamethyleneimine ring.Examples of a ring formed by binding R₂₅ and R₂₆ through a heteroatomtogether with a nitrogen atom to which they are bound include amorpholine ring and a piperazine ring. Examples of a ring formed bybinding R₂₅ and R₂₆ through an aromatic ring together with a nitrogenatom to which they are bound include a tetrahydroisoquinoline ring and atetrahydroindole ring.

When R₂₅ and/or R₂₆ is a group represented by the formula (8) and R₂₉and G form a ring, examples of R₂₅ and R₂₆ include a tetralinyl group,an indanyl group, a tetrahydroquinolyl group, and atetrahydroisoquinolyl group.

Examples of the “substitutable” groups in the expressions for eachsubstituent include a hydroxyl group, a thiol group, a formyl group, acarboxyl group, a sulfonyl group, an amino group, an amide group, acarbamoyl group, a cyano group, an alkoxy group, an alkoxycarbonylgroup, an alkylamino group, an acylamino group, an alkoxycarbonylaminogroup, alkylthio group, an aminosulfonyl group, a dialkylaminosulfonylgroup, a methanesulfonyl group, a p-toluenesulfonyl group, and a phenylgroup. The alkoxy group represents a group in which an alkyl group bindsthrough an oxygen atom, and the acylamino group represents a group inwhich an alkyl group or a phenyl group binds to an amino group through acarbonyl group. Further, examples of the “substitutable” groups in A₁and A₂ include an alkyl group, a hydroxyalkyl group, an alkoxyalkylgroup, and an aminoalkyl group other than the group described above.

The prodrug is a precursor substance that becomes an effective drugthrough biochemical metabolism after administration to the living body.Specifically, the prodrug is a compound which is obtained by binding oneor more appropriate groups, that is eliminated by metabolism in theliving body, such as alkoxycarbonyl group or dialkylaminosulfone groupwith N in the ring or chain of a heterocycle or the like contained inthe compound represented by the general formula (1). Alternatively, theprodrug is a compound coupled with one or more ester groups or the likethat utilize alcohol or carboxylic acid, which may be contained in thecompound represented by the general formula (1).

In addition, pharmacologically acceptable salts includetrifluoroacetates, hydrochlorides, acetates, sulfates, nitrates,lactates, maleates, methane sulfonates, toluene sulfonates, tartrates,citrates, oxalates, malonates, succinates, fumarates, propionates,butyrates, glucuronates, terephthalates, and phosphorates.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1–24 illustrate process steps of production methods describedbelow for several compounds of the present invention. In other words,FIGS. 1 to 24 show reaction process steps of Production Method Examples1–24, respectively.

BEST MODE FOR CARRYING OUT THE INVENTION

Compounds of the present invention can be produced by organic chemicalreactions generally employed in the art. Hereinafter, production methodstherefor will be exemplified with reference to the accompanyingdrawings, FIGS. 1–24. However, the synthesis of the compounds of thepresent invention is not limited to these methods.

PRODUCTION METHOD EXAMPLE 1

The reaction process steps of Production Method Example 1 are shown inFIG. 1.

Step 1-1

An easily obtainable compound (I-1) is reacted with commerciallyavailable 2-imidazole carboxaldehyde and an appropriate reductant suchas sodium cyanoborohydride in an appropriate solvent such as methanol toobtain a compound (I-2).

Step 1-2

The compound (I-2) is reacted with commercially available di-t-butyldicarbonate and an appropriate base such as triethylamine in anappropriate solvent such as chloroform to thereby obtain a compound(I-3).

Step 1-3

The compound (I-3) is reacted with an appropriate base such as a sodiumhydroxide aqueous solution in an appropriate solvent such as methanol tothereby obtain a compound (I-4).

Step 1-4

An easily obtainable compound (I-5) is reacted with commerciallyavailable propionaldehyde, an appropriate dehydrating agent such astrimethyl orthoformate, and an appropriate reductant such as sodiumcyanoborohydride in an appropriate solvent such as methanol to therebyobtain a compound (I-6).

Step 1-5

The compound (I-6) is deprotected by reaction with an appropriate acidsuch as a hydrogen chloride/dioxane solution in an appropriate solventsuch as methanol. Then, the resultant is reacted with the compound (I-4)and an appropriate condensing agent such as commercially available1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimide (hereinafter, referredto as WSCI)/1-hydroxy benzotriazole (hereinafter, referred to as HOBt)in an appropriate solvent such as chloroform to thereby obtain acompound (I-7).

Step 1-6

The compound (I-7) is deprotected by reaction with an appropriate acidsuch as a hydrogen chloride/dioxane solution in an appropriate solventsuch as methanol to thereby obtain a compound (I-8).

Step 1-7

Easily obtainable aldehyde A₂-CHO (A₂ is as described above) is reactedwith the compound (I-8), an appropriate dehydrating agent such astrimethyl orthoformate, and an appropriate reductant such as sodiumcyanoborohydride in an appropriate solvent such as methanol to therebyobtain a compound (I-9) represented by the general formula (1).

Step 1-8

A commercially available compound (I-10) is reacted with commerciallyavailable propionaldehyde and an appropriate reductant such as sodiumcyanoborohydride in an appropriate solvent such as methanol to therebyobtain the compound (I-11).

Step 1-9

The compound (I-11) is reacted with an appropriate reductant such ashydrazine monohydrate in an appropriate solvent such asmethanol/tetrahydrofuran (hereinafter, referred to as THF) to therebyobtain a compound (I-12).

Step 1-10

The compound (I-12) is reacted with the compound (I-4) and anappropriate condensing agent such as commercially availablePS-carbodiimide/HOBt in an appropriate solvent such as DMF to therebyobtain a compound (I-13).

Step 1-11

An easily obtainable aldehyde A₂-CHO (A₂ is as described above) isreacted with the compound (I-13) and an appropriate reductant such assodium cyanoborohydride in an appropriate solvent such as methanol tothereby obtain a compound (I-14) represented by the general formula (1).

Step 1-12

A commercially available compound (I-10) is reacted with commerciallyavailable cyclohexanone, an appropriate dehydrating agent such astrimethyl orthoformate, and an appropriate reductant such as sodiumcyanoborohydride in an appropriate solvent such as methanol to therebyobtain a compound (I-15).

Step 1-13

The compound (I-15) is reacted with commercially availablebenzyloxycarbonyl chloride and an appropriate base such as a sodiumhydroxide aqueous solution in an appropriate solvent such as dioxane toobtain a benzyloxycarbonyl (hereinafter, referred to as Cbz) protectingsubstance, followed by the reaction with an appropriate reductant suchas hydrazine monohydrate in an appropriate solvent such as methanol/THFto thereby obtain a compound (I-16).

Step 1-14

The compound (I-16) is reacted with the compound (I-4) and anappropriate condensing agent such as commercially available WSCI/HOBt inan appropriate solvent such as chloroform and then deprotected byreaction with an appropriate acid such as a hydrogen chloride/dioxanesolution in an appropriate solvent such as methanol to thereby obtain acompound (I-17).

Step 1-15

An easily obtainable aldehyde A₂-CHO (A₂ is as described above) isreacted with the compound (I-17) and an appropriate reductant such assodium cyanoborohydride in an appropriate solvent such as methanol andthen deprotected by reaction with an appropriate reductant such as 10%palladium-carbon under hydrogen atmosphere in an appropriate solventsuch as ethanol to thereby obtain a compound (I-18), which is a compoundrepresented by the general formula (1).

PRODUCTION METHOD EXAMPLE 2

The reaction process steps of Production Method Example 2 are shown inFIG. 2.

Step 2-1

The compound (I-4) is deprotected and esterified by reaction with anappropriate acid such as hydrochloric acid in an appropriate solventsuch as methanol to thereby obtain a compound (I-2).

Step 2-2

The compound (I-2) is reacted with 2-imidazole carboxaldehyde and anappropriate reductant such as sodium cyanoborohydride in an appropriatesolvent such as methanol and then reacted with an appropriate base suchas a sodium hydroxide aqueous solution in an appropriate solvent such asmethanol to thereby obtain a compound (II-1).

Step 2-3

An easily obtainable compound (II-2) is reacted with commerciallyavailable isobutylaldehyde and an appropriate reductant such as sodiumcyanoborohydride in an appropriate solvent such as methanol to therebyobtain a compound (II-3).

Step 2-4

The compound (II-3) is deprotected by reaction with an appropriatereductant such as 10% palladium-carbon under hydrogen atmosphere in anappropriate solvent such as ethanol. Then, the resultant is reacted withthe compound (II-1) and an appropriate condensing agent such ascommercially available dicyclohexylcarbodiimide (hereinafter, referredto as DCC)/HOBt in an appropriate solvent such as DMF to thereby obtaina compound (II-4) which is a compound represented by the general formula(1).

Step 2-5

An easily obtainable compound (II-5) is reacted with commerciallyavailable propionaldehyde and an appropriate reductant such as sodiumcyanoborohydride in an appropriate solvent such as methanol to therebyobtain a compound (II-6).

Step 2-6

The compound (II-6) is deprotected by reaction with an appropriate acidsuch as hydrochloric acid in an appropriate solvent such as methanol andthen reacted with the compound (II-1) and an appropriate condensingagent such as DCC/HOBt in an appropriate solvent such as DMF to therebyobtain a compound (II-7) which is a compound represented by the generalformulation (1).

Step 2-7

The compound (I-12) is reacted with formic acid in an appropriatesolvent such as acetic anhydride/THF and then reacted with anappropriate reductant such as lithium aluminum hydride in an appropriatesolvent such as THF to thereby obtain a compound (II-8).

Step 2-8

The compound (II-8) is reacted with the compound (II-1) and anappropriate condensing agent such as DCC/HOBt in an appropriate solventsuch as DMF to thereby obtain a compound (II-9) which is a compoundrepresented by the general formula (1).

Step 2-9

A commercially available compound (II-10) is reacted with commerciallyavailable propionaldehyde, an appropriate dehydrating agent such astrimethyl orthoformate, and an appropriate reductant such as sodiumcyanoborohydride in an appropriate solvent such as methanol to therebyobtain a compound (II-11).

Step 2-10

The compound (II-11) is deprotected by reaction with an appropriatereductant such as 10% palladium-carbon under hydrogen atmosphere in anappropriate solvent such as ethanol. Then, the resultant is reacted withthe compound (II-1) and an appropriate condensing agent such as DCC/HOBtin an appropriate solvent such as DMF to thereby obtain a compound(II-12) which is a compound represented by the general formula (1).

PRODUCTION METHOD EXAMPLE 3

The reaction process steps of Production Method Example 3 are shown inFIG. 3.

Step 3-1

The compound (II-1) is reacted with the compound (I-5) and anappropriate condensing agent such as DCC/HOBt in an appropriate solventsuch as DMF and then deprotected by reaction with an appropriate acidsuch as hydrochloric acid in an appropriate solvent such as methanol tothereby obtain a compound (III-1).

Step 3-2

The compound (III-1) is reacted with easily obtainable aldehyde orketone corresponding to R₂₅ and R₂₆ (R₂₅ and R₂₆ are as describedabove), an appropriate dehydrating agent such as trimethyl orthoformate,and an appropriate reductant such as sodium cyanoborohydride in anappropriate solvent such as DMF to thereby obtain a compound (III-2)which is a compound represented by the general formula (1).

Step 3-3

The compound (II-1) is reacted with commercially available1-t-butoxycarbonyl-piperazine and an appropriate condensing agent suchas WSCI/HOBt in an appropriate solvent such as DMF, and then deprotectedby reaction with an appropriate acid such as hydrochloric acid in anappropriate solvent such as methanol to thereby obtain a compound(III-3).

Step 3-4

The compound (III-3) is reacted with easily obtainable aldehyde orketone corresponding to R₁₃ (R₁₃ is as described above), an appropriatedehydrating agent such as trimethyl orthoformate, and an appropriatereductant such as sodium cyanoborohydride in an appropriate solvent suchas DMF to thereby obtain a compound (III-4) which is a compoundrepresented by the general formula (1).

PRODUCTION METHOD EXAMPLE 4

The reaction process steps of Production Method Example 4 are shown inFIG. 4.

Step 4-1

The compound (I-1) is reacted with an appropriate reductant such aslithium aluminum hydride in an appropriate solvent such as THF tothereby obtain a compound (IV-1).

Step 4-2

The compound (IV-1) is reacted with commercially availableN-carbethoxyphthalimide and an appropriate base such as sodium carbonatein an appropriate solvent such as THF/water to thereby obtain a compound(IV-2).

Step 4-3

The compound (IV-2) is reacted with an appropriate oxidant such asmanganese dioxide in an appropriate solvent such as chloroform tothereby obtain a compound (IV-3).

Step 4-4

The compound (I-12) is reacted with the compound (IV-3) and anappropriate reductant such as sodium cyanoborohydride in an appropriatesolvent such as methanol and then t-butoxycarbonylated (hereinafter,butoxycarbonyl is referred to as Boc) by reaction with commerciallyavailable di-t-butyl dicarbonate, and an appropriate base such astriethylamine in an appropriate solvent such as DMF, and further reactedwith an appropriate base such as an aqueous methylamine solution in anappropriate solvent such as methanol to thereby obtain a compound(IV-4).

Step 4-5

Easily obtainable aldehyde A₁-CHO when A₁ and A₂ are identical or easilyobtainable A₁-CHO and A₂-CHO when A₁ and A₂ are not identical (A₁ and A₂are as described above) is/are separately one after another reacted withthe compound (IV-4) and an appropriate reductant such as sodiumcyanoborohydride in an appropriate solvent such as methanol, and thendeprotected by reaction with an appropriate acid such as hydrochloricacid in an appropriate solvent such as methanol to thereby obtain acompound (IV-5) which is a compound represented by the general formula(1).

Step 4-6

A compound (IV-6), which is obtained by deprotecting the compound (I-6)with acid, is reacted with the compound (IV-3) and an appropriatereductant such as sodium cyanoborohydride in an appropriate solvent suchas methanol, then t-butoxycarbonylated by reaction with commerciallyavailable di-t-butyl dicarbonate and an appropriate base such astriethylamine in an appropriate solvent such as DMF, and further reactedwith an appropriate base such as an aqueous methylamine solution in anappropriate solvent such as methanol to thereby obtain a compound(IV-7).

Step 4-7

Easily obtainable aldehyde A₁-CHO when A₁ and A₂ are identical or easilyobtainable A₁-CHO and A₂-CHO when A₁ and A₂ are not identical (A₁ and A₂are as described above) is/are separately one after another reacted withthe compound (IV-7) and an appropriate reductant such as sodiumcyanoborohydride in an appropriate solvent such as methanol, and thendeprotected by reaction with an appropriate acid such as hydrochloricacid in an appropriate solvent such as methanol to thereby obtain acompound (IV-8) which is a compound represented by the general formula(1).

Step 4-8

A commercially available compound (IV-9) is reacted with commerciallyavailable N-carbethoxyphthalimide and an appropriate base such as sodiumcarbonate in an appropriate solvent such as water to thereby obtain acompound (IV-10).

Step 4-9

The compound (IV-10) is reacted with chlorosulfonic acid in anappropriate solvent such as chloroform to thereby obtain a compound(IV-11).

Step 4-10

The compound (IV-11) is reacted with phosphorous pentachloride, tothereby obtain a compound (IV-12).

Step 4-11

The compound (IV-12) is reacted with the compound (IV-6) and anappropriate base such as triethylamine in an appropriate solvent such aschloroform, and then reacted with an appropriate reductant such as anaqueous methylamine solution in an appropriate solvent such as methanolto thereby obtain a compound (IV-13).

Step 4-12

Easily obtainable aldehyde A₁-CHO when A₁ and A₂ are identical or easilyobtainable A₁-CHO and A₂-CHO when A₁ and A₂ are not identical (A₁ and A₂are as described above) is/are separately one after another reacted withthe compound (IV-13) and an appropriate reductant such as sodiumcyanoborohydride in an appropriate solvent such as methanol to therebyobtain a compound (IV-14) which is a compound represented by the generalformula (1).

PRODUCTION METHOD EXAMPLE 5

The reaction process steps of Production Method Example 5 are shown inFIG. 5.

Step 5-1

The compound (I-4) is esterified and then reacted with an appropriatereductant such as lithium aluminum hydride in an appropriate solventsuch as THF to thereby obtain a compound (V-1).

Step 5-2

The compound (V-1) is reacted with commercially availablemethanesulfonyl chloride and an appropriate base such asdiisopropylethylamine in an appropriate solvent such as dichloromethaneto thereby obtain a compound (V-2).

Step 5-3

A commercially available compound (V-3) is reacted with commerciallyavailable propionaldehyde and an appropriate reductant such as sodiumcyanoborohydride in an appropriate solvent such as methanol to therebyobtain a compound (V-4).

Step 5-4

The compound (V-4) is reacted with the compound (V-1) and an appropriateMitsunobu reagent such as triphenylphosphine/diethylazodicarboxylate inan appropriate solvent such as THF to thereby obtain a compound (V-5).

Step 5-5

The compound (V-5) is deprotected by reaction with an appropriate acidsuch as hydrochloric acid in an appropriate solvent such as methanol.Then, the resultant is reacted with an easily obtainable aldehyde A₂-CHO(A₂ is as described above) and an appropriate reductant such as sodiumcyanoborohydride in an appropriate solvent such as methanol to therebyobtain a compound (V-6) which is a compound represented by the generalformula (1).

Step 5-6

A compound (V-7), which is obtained such that commercially available4-aminomethylbenzoic acid is esterified and subjected to reductivecondensation reaction with propionaldehyde, is reacted with anappropriate reductant such as lithium aluminum hydride in an appropriatesolvent such as THF to thereby obtain a compound (V-8).

Step 5-7

The compound (V-8) is reacted with the compound (V-2) and an appropriatebase such as potassium carbonate in an appropriate solvent such as DMF,then deprotected by reaction with an appropriate acid such ashydrochloric acid in an appropriate solvent such as methanol, andfurther reacted with easily obtainable aldehyde A₂-CHO (A₂ is asdescribed above) and an appropriate reductant such as sodiumcyanoborohydride in an appropriate solvent such as methanol to therebyobtain a compound (V-9) which is a compound represented by the generalformula (1).

Step 5-8

A commercially available compound (V-10) is reacted with commerciallyavailable propionaldehyde and an appropriate reductant such as sodiumcyanoborohydride in an appropriate solvent such as methanol to therebyobtain a compound (V-11).

Step 5-9

The compound (V-11) is reacted with the compound (V-2) and anappropriate base such as potassium carbonate in an appropriate solventsuch as DMF, then deprotected by reaction with an appropriate acid suchas hydrochloric acid in an appropriate solvent such as methanol, andfurther reacted with easily obtainable aldehyde A₂-CHO (A₂ is asdescribed above) and an appropriate reductant such as sodiumcyanoborohydride in an appropriate solvent such as methanol to therebyobtain a compound (V-12) which is a compound represented by the generalformula (1).

Step 5-10

A commercially available compound (V-13) is reacted with commerciallyavailable propionaldehyde and an appropriate reductant such as sodiumcyanoborohydride in an appropriate solvent such as methanol to therebyobtain a compound (V-14).

Step 5-11

The compound (V-14) is reacted with the compound (V-2) and anappropriate base such as potassium bicarbonate in an appropriate solventsuch as dichloromethane, then deprotected by reaction with anappropriate acid such as hydrochloric acid in an appropriate solventsuch as methanol, and further reacted with easily obtainable aldehydeA₂-CHO (A₂ is as described above) and an appropriate reductant such assodium cyanoborohydride in an appropriate solvent such as methanol tothereby obtain a compound (V-15) which is a compound represented by thegeneral formula (1).

PRODUCTION METHOD EXAMPLE 6

The reaction process steps of Production Method Example 6 are shown inFIG. 6.

Step 6-1

The commercially available compound (VI-1) is reacted with commerciallyavailable di-t-butyl dicarbonate and an appropriate base such astriethylamine in an appropriate solvent such as dichloromethane tothereby obtain a compound (VI-2).

Step 6-2

A commercially available compound (VI-3) is reacted with commerciallyavailable propionaldehyde, an appropriate dehydrating agent such astrimethyl orthoformate, and an appropriate reductant such as sodiumcyanoborohydride in an appropriate solvent such as methanol to therebyobtain a compound (VI-4).

Step 6-3

The compound (VI-2) is reacted with the compound (VI-4) and anappropriate condensing agent such as WSCI/HOBt in an appropriate solventsuch as DMF to thereby obtain a compound (VI-5).

Step 6-4

A compound (VI-5) is deprotected by reaction with an appropriate acidsuch as hydrochloric acid in an appropriate solvent such as methanol,and then easily obtainable aldehyde A₁-CHO when A₁ and A₂ are identicalor easily obtainable A₁-CHO and A₂-CHO when A₁ and A₂ are not identical(A₁ and A₂ are as described above) is/are separately one after anotherreacted with an appropriate reductant such as sodium cyanoborohydride inan appropriate solvent such as methanol to thereby obtain a compound(VI-6) which is a compound represented by the general formula (1).

PRODUCTION METHOD EXAMPLE 7

The reaction process steps of Production Method Example 7 are shown inFIG. 7.

Step 7-1

A commercially available compound (VII-1) is reacted with an appropriateoxidant such as m-chloroperbenzoic acid in an appropriate solvent suchas dichloromethane to thereby obtain a compound (VII-2).

Step 7-2

The compound (VII-2) is reacted with trifluoroacetic anhydride in anappropriate solvent such as dichloromethane to thereby obtain a compound(VII-3).

Step 7-3

The compound (VII-3) is reacted with an appropriate base such as sodiummethoxide in an appropriate solvent such as methanol to thereby obtain acompound (VII-4).

Step 7-4

The compound (VII-4) is reacted with an appropriate oxidant such asmanganese dioxide in an appropriate solvent such as chloroform tothereby obtain a compound (VII-5) which is raw material aldehyde A₂-CHO(A₂ is as described above).

Step 7-5

A commercially available compound (VII-6) is esterified to therebyobtain a compound (VII-7).

Step 7-6

The compound (VII-7) is reacted with an appropriate reductant such assodium borohydride in an appropriate solvent such as ethanol/THF tothereby obtain a compound (VII-8).

Step 7-7

The compound (VII-8) is reacted with an appropriate oxidant such asmanganese dioxide in an appropriate solvent such as chloroform tothereby obtain a compound (VII-9) which is raw material aldehyde A₁-CHO(A₁ is as described above).

PRODUCTION METHOD EXAMPLE 8

The reaction process steps of Production Method Example 8 are shown inFIG. 8.

Step 8-1

A compound (VIII-1) is reacted with a prodrug reagent such as ethylchloroformate and an appropriate base such as triethylamine in anappropriate solvent such as chloroform to thereby obtain a compound(VIII-2) and a compound (VIII-3), which are the compounds represented bythe general formula (1) and prodrugs.

PRODUCTION METHOD EXAMPLE 9

The reaction process steps of Production Method Example 9 are shown inFIG. 9.

Step 9-1

A compound (IV-8) is reacted with easily obtainable aldehyde R₁₁—CHO(R₁₁ is as described above) and an appropriate reductant such as sodiumcyanoborohydride in an appropriate solvent such as methanol to therebyobtain a compound (IX-1) which is a compound represented by the generalformula (1).

PRODUCTION METHOD EXAMPLE 10

The reaction process steps of Production Method Example 10 are shown inFIG. 10.

Step 10-1

A commercially available compound (I-5) is reacted with commerciallyavailable cyclohexane and an appropriate reductant such as sodiumcyanoborohydride in an appropriate solvent such as methanol to therebyobtain a compound (X-2).

Step 10-2

The compound (X-2) is reacted with a commercially available aqueousformaldehyde solution and an appropriate reductant such as sodiumcyanoborohydride in an appropriate solvent such as methanol to therebyobtain a compound (X-3).

Step 10-3

The compound (X-3) is deprotected by reaction with an appropriate acidsuch as a hydrogen chloride/dioxane solution in an appropriate solventsuch as methanol, and then reacted with the compound (II-1) and anappropriate condensing agent such as WSCI/HOBt in an appropriate solventsuch as DMF to thereby obtain a compound (X-4).

Step 10-4

The compound (X-3) is deprotected by reaction with an appropriate acidsuch as a hydrogen chloride/dioxane solution in an appropriate solventsuch as methanol, and then reacted with the compound (I-4) and anappropriate condensing agent such as WSCI/HOBt in an appropriate solventsuch as chloroform to thereby obtain a compound (X-5).

Step 10-5

The compound (X-5) is reacted with an appropriate acid such as ahydrogen chloride/dioxane solution in an appropriate solvent such asmethanol to thereby obtain a compound (X-6).

Step 10-6

The compound (X-6) is reacted with easily obtainable aldehyde A₂-CHO (A₂is as described above) and an appropriate reductant such as sodiumcyanoborohydride in an appropriate solvent such as methanol to therebyobtain a compound (X-7) which is a compound represented by the generalformula (1).

PRODUCTION METHOD EXAMPLE 11

The reaction process steps of Production Method Example 11 are shown inFIG. 11.

Step 11-1

The compound (IV-12) is reacted with the compound (I-5) and anappropriate base such as triethylamine in an appropriate solvent such aschloroform, and then further reacted with an appropriate base such asmethylamine in an appropriate solvent such as methanol to thereby obtaina compound (XI-1).

Step 11-2

Easily obtainable aldehyde A₁-CHO when A₁ and A₂ are identical or easilyobtainable aldehydes A₁-CHO and A₂-CHO when A₁ and A₂ are not identical(A₁ and A₂ are as described above) is/are separately one after anotherreacted with the compound (XI-1) and an appropriate reductant such assodium cyanoborohydride in an appropriate solvent such as methanol tothereby obtain a compound (XI-2) which is a compound represented by thegeneral formula (1).

Step 11-3

The compound (XI-2), which is a compound represented by the generalformula (1), is reacted with an appropriate acid such as a hydrogenchloride/dioxane solution in an appropriate solvent such as methanol tothereby obtain a compound (XI-3) which is a compound represented by thegeneral formula (1).

Step 11-4

The compound (XI-3) which is a compound represented by the generalformula (1) is reacted with an easily obtainable aldehyde or ketonecorresponding to R₂₅ and R₂₆ (R₂₅ and R₂₆ are as described above), andan appropriate reductant such as sodium cyanoborohydride in anappropriate solvent such as methanol to thereby obtain a compound (XI-4)which is a compound represented by the general formula (1).

Step 11-5

A compound (IV-6), which is prepared by deprotecting the compound (I-6)with acid, is reacted with a formylating agent such as a mixture offormic acid and acetic anhydride in an appropriate solvent such as THFto thereby obtain a compound (XI-5).

Step 11-6

The compound (XI-5) is reacted with an appropriate reductant such aslithium aluminum hydride in an appropriate solvent such as THF tothereby obtain a compound (XI-6).

Step 11-7

The compound (XI-6) is reacted with the compound (IV-12) and anappropriate base such as triethylamine in an appropriate solvent such aschloroform, and then reacted with an appropriate reductant such as anaqueous methylamine solution in an appropriate solvent such as methanolto thereby obtain a compound (XI-7).

Step 11-8

Easily obtainable aldehyde A₁-CHO when A₁ and A₂ are identical or easilyobtainable aldehydes A₁-CHO and A₂-CHO when A₁ and A₂ are not identical(A₁ and A₂ are as described above) is/are separately one after anotherreacted with the compound (XI-7) and an appropriate reductant such assodium cyanoborohydride in an appropriate solvent such as methanol tothereby obtain a compound (XI-8) which is a compound represented by thegeneral formula (1).

PRODUCTION METHOD EXAMPLE 12

The reaction process steps of Production Method Example 12 are shown inFIG. 12.

Step 12-1

The easily obtainable compound (I-1) is reacted with commerciallyavailable di-t-butyl dicarbonate and an appropriate base such astriethylamine in an appropriate solvent such as chloroform to therebyobtain a compound (XII-1).

Step 12-2

The compound (XII-1) is reacted with an appropriate reductant such aslithium aluminum hydride in an appropriate solvent such as THF tothereby obtain a compound (XII-2).

Step 12-3

The compound (XII-2) is reacted with an appropriate oxidant such asmanganese dioxide in an appropriate solvent such as chloroform tothereby obtain a compound (XII-3).

Step 12-4

The compound (XII-3) is reacted with the compound (II-2), an appropriatedehydrating agent such as trimethyl orthoformate, and an appropriatereductant such as sodium borohydride in an appropriate solvent such asmethanol to thereby obtain a compound (XII-4).

Step 12-5

The compound (XII-4) is reacted with an aqueous formaldehyde solutionand an appropriate reductant such as sodium cyanoborohydride in anappropriate solvent such as methanol to thereby obtain a compound(XII-5).

Step 12-6

The compound (XII-5) is reacted with an appropriate acid such as ahydrogen chloride/dioxane solution in an appropriate solvent such asmethanol, to thereby obtain a compound (XII-6).

Step 12-7

Easily obtainable aldehyde A₁-CHO when A₁ and A₂ are identical or easilyobtainable aldehydes A₁-CHO and A₂-CHO when A₁ and A₂ are not identical(A₁ and A₂ are as described above) is/are separately one after anotherreacted with the compound (XII-6) and an appropriate reductant such assodium cyanoborohydride in an appropriate solvent such as methanol tothereby obtain a compound (XII-7) which is a the compound represented bythe general formula (1).

Step 12-8

The compound (XII-7) which is a compound represented by the generalformula (1) is reacted with an appropriate reductant such as 10%palladium-carbon under a hydrogen atmosphere in an appropriate solventsuch as ethanol to thereby obtain a compound (XII-8) which is a compoundrepresented by the general formula (1).

Step 12-9

The compound (XII-8) which is a compound represented by the generalformula (1) is reacted with an easily obtainable aldehyde or ketonecorresponding to R₂₅ and R₂₆ (R₂₅ and R₂₆ are as described above), andan appropriate reductant such as sodium cyanoborohydride in anappropriate solvent such as methanol to thereby obtain a compound(XII-9) which is a compound represented by the general formula (1).

Step 12-10

The compound (XI-6) is reacted with the compound (I-4) and anappropriate condensing agent such as WSCI/HOBt in an appropriate solventsuch as chloroform to thereby obtain a compound (XII-10).

Step 12-11

The compound (XII-10) is reacted with an appropriate acid such as ahydrogen chloride/dioxane solution in an appropriate solvent such asmethanol to thereby obtain a compound (XII-11).

Step 12-12

The compound (XII-11) is reacted with an easily obtainable aldehydeA₂-CHO (A₂ is as described above) and an appropriate reductant such assodium cyanoborohydride in an appropriate solvent such as methanol tothereby obtain a compound (XII-12) which is a compound represented bythe general formula (1).

PRODUCTION METHOD EXAMPLE 13

The reaction process steps of Production Method Example 13 are shown inFIG. 13.

Step 13-1

The compound (VI-1) is reacted with an appropriate oxidant such asmanganese dioxide in an appropriate solvent such as dichloromethane, tothereby obtain a compound (XIII-1).

Step 13-2

The compound (I-5) is reacted with commercially available 2-imidazolecarboxaldehyde, an appropriate dehydrating agent such as trimethylorthoformate, and an appropriate reductant such as sodium borohydride inan appropriate solvent such as methanol to thereby obtain a compound(XIII-2).

Step 13-3

The compound (XIII-2) is reacted with commercially available1-methyl-2-imidazole carboxaldehyde, an appropriate acid such as aceticacid, and an appropriate reductant such as sodium cyanoborohydride in anappropriate solvent such as methanol to thereby obtain a compound(XIII-3).

Step 13-4

The compound (XIII-3) is reacted with an appropriate acid such ashydrochloric acid in an appropriate solvent such as methanol to therebyobtain a compound (XIII-4).

Step 13-5

The compound (XIII-4) is reacted with the compound (XIII-1), anappropriate dehydrating agent such as trimethyl orthoformate and anappropriate reductant such as sodium borohydride in an appropriatesolvent such as methanol to thereby obtain a compound (XIII-5).

Step 13-6

The compound (XIII-5) is reacted with a commercially available aqueousformaldehyde solution, an appropriate dehydrating agent such astrimethyl orthoformate, and an appropriate reductant such as sodiumborohydride in an appropriate solvent such as methanol to thereby obtaina compound (XIII-6) which is a compound represented by the generalformula (1).

PRODUCTION METHOD EXAMPLE 14

The reaction process steps of Production Method Example 14 are shown inFIG. 14.

Step 14-1

The compound (IV-6), which is prepared by deprotecting the compound(I-6) with acid, is reacted with the compound (XII-3), an appropriatedehydrating agent such as trimethyl orthoformate and an appropriatereductant such as sodium borohydride in an appropriate solvent such asmethanol to thereby obtain a compound (XIV-1).

Step 14-2

The compound (XIV-1) is reacted with an aqueous formaldehyde solutionand an appropriate reductant such as sodium cyanoborohydride in anappropriate solvent such as methanol to thereby obtain a compound(XIV-2).

Step 14-3

The compound (XIV-2) is deprotected by a reaction with an appropriateacid such as a hydrogen chloride/dioxane solution, and then easilyobtainable aldehyde A₁-CHO when A₁ and A₂ are identical or easilyobtainable A₁-CHO and A₂-CHO when A₁ and A₂ are not identical (A₁ and A₂are as described above) is/are separately one after another reacted withan appropriate reductant such as sodium cyanoborohydride in anappropriate solvent such as methanol to thereby obtain a compound(XIV-3) which is a compound represented by the general formula (1).

PRODUCTION METHOD EXAMPLE 15

The reaction process steps of Production Method Example 15 are shown inFIG. 15.

Step 15-1

The commercially available compound (VI-3) is reacted with di-t-butyldicarbonate and an appropriate base such as a sodium hydroxide aqueoussolution in an appropriate solvent such as dioxane to thereby obtain acompound (XV-1).

Step 15-2

The compound (XV-1) is reacted with the compound (I-12) and anappropriate condensing agent such as WSCI in an appropriate solvent suchas chloroform, to thereby obtain a compound (XV-2).

Step 15-3

The compound (XV-2) is deprotected by a reaction with an appropriateacid such as a hydrogen chloride/dioxane solution, and then easilyobtainable aldehyde A₁-CHO when A₁ and A₂ are identical or easilyobtainable A₁-CHO and A₂-CHO when A₁ and A₂ are not identical (A₁ and A₂are as described above) is/are separately one after another reacted withan appropriate reductant such as sodium cyanoborohydride in anappropriate solvent such as methanol to thereby obtain a compound (XV-3)which is a compound represented by the general formula (1).

PRODUCTION METHOD EXAMPLE 16

The reaction process steps of Production Method Example 16 are shown inFIG. 16.

Step 16-1

A commercially available compound (XVI-1) is reacted with an appropriateoxidant such as meta-chloroperbenzoic acid in an appropriate solventsuch as dichloromethane to thereby obtain a compound (XVI-2).

Step 16-2

The compound (XVI-2) is reacted with trifluoroacetic anhydride in anappropriate solvent such as dichloromethane to thereby obtain a compound(XVI-3).

Step 16-3

The compound (XVI-3) is reacted with an appropriate base such as sodiummethoxide in an appropriate solvent such as methanol to thereby obtain acompound (XVI-4).

Step 16-4

The compound (XVI-4) is reacted with an appropriate oxidant such asmanganese dioxide in an appropriate solvent such as chloroform tothereby obtain a compound (XVI-5) which is raw material aldehyde A₂-CHO(A₂ is as described above).

Step 16-5

A commercially available compound (XVI-6) is reacted with an appropriateoxidant such as meta-chloroperbenzoic acid in an appropriate solventsuch as dichloromethane to thereby obtain a compound (XVI-7).

Step 16-6

The compound (XVI-7) is reacted with trifluoroacetic anhydride in anappropriate solvent such as dichloromethane to thereby obtain a compound(XVI-8).

Step 16-7

The compound (XVI-8) is reacted with an appropriate base such as sodiummethoxide in an appropriate solvent such as methanol to thereby obtain acompound (XVI-9).

Step 16-8

The compound (XVI-9) is reacted with an appropriate oxidant such asmanganese dioxide in an appropriate solvent such as chloroform tothereby obtain a compound (XVI-10) which is raw material aldehyde A₁-CHO(A₁ is as described above).

PRODUCTION METHOD EXAMPLE 17

The reaction process steps of Production Method Example 17 are shown inFIG. 17.

Step 17-1

An easily obtainable compound (XVII-1) is reacted with5-t-butoxycarbonylaminovaleric acid, an appropriate condensing agent andcatalyst such as WSCI or HOBt in an appropriate solvent such as DMF tothereby obtain a compound (XVII-2).

Step 17-2

The compound (XVII-2) is reacted in an appropriate solvent such asmethanol in the presence of an appropriate acid such as hydrochloricacid. Then, the resultant is reacted with propionaldehyde, anappropriate reductant such as sodium cyanoborohydride, and anappropriate dehydrating agent such as trimethyl orthoformate in anappropriate solvent such as methanol to thereby obtain a compound(XVII-3).

Step 17-3

The compound (XVII-3) is reacted with an appropriate reductant such aslithium aluminum hydride in an appropriate solvent such as THF, and thenreacted with p-toluenesulfonyl chloride and an appropriate base such astriethylamine in an appropriate solvent such as dichloromethane tothereby obtain a compound (XVII-4).

Step 17-4

The compound (XVII-4) is reacted with potassium phthalimide in anappropriate solvent such as DMF, and then reacted with an appropriatebase such as methylamine in an appropriate solvent such as methanol tothereby obtain a compound (XVII-5).

Step 17-5

The compound (XVII-5) is reacted with commercially available 2-imidazolecarboxaldehyde, an appropriate reductant such as sodium borohydride, andan appropriate dehydrating agent such as trimethyl orthoformate in anappropriate solvent such as methanol, and then reacted with commerciallyavailable 1-methyl-2-imidazole carboxaldehyde, an appropriate reductantsuch as sodium borohydride, and an appropriate dehydrating agent such astrimethyl orthoformate or an appropriate acid catalyst such as aceticacid in an appropriate solvent such as methanol to thereby obtain acompound (XVII-6) which is a compound represented by the general formula(1).

PRODUCTION METHOD EXAMPLE 18

The reaction process steps of Production Method Example 18 are shown inFIG. 18.

Step 18-1

A commercially available compound (XVIII-1) is reacted withN-bromosuccinimide and an appropriate radical generator such asazobisisobutyronitrile in an appropriate solvent such as carbontetrachloride to thereby obtain a compound (XVIII-2).

Step 18-2

The compound (XVIII-2) is reacted with potassium phthalimide in anappropriate solvent such as DMF to thereby obtain a compound (XVIII-3).

Step 18-3

The compound (XVIII-3) is reacted with an appropriate oxidant such asmeta-chloroperbenzoic acid in an appropriate solvent such as chloroform,resulting in a compound (XVIII-4).

Step 18-4

The compound (XVIII-4) is reacted with appropriate acid anhydride suchas trifluoroacetic anhydride in an appropriate solvent such asdichloromethane, and then reacted with an appropriate base such assodium hydrogen carbonate in an appropriate solvent such as methanol tothereby obtain a compound (XVIII-5).

Step 18-5

The compound (XVIII-5) is reacted with an appropriate oxidant such asmanganese dioxide in an appropriate solvent such as chloroform tothereby obtain a compound (XVIII-6).

Step 18-6

The compound (XVIII-6) is reacted with triphenylphosphonylideneacetonitrile in an appropriate solvent such as THF tothereby obtain a compound (XVIII-7).

Step 18-7

The compound (XVIII-7) is reacted, under hydrogen atmosphere, with anappropriate catalyst such as palladium hydroxide-carbon in anappropriate solvent such as ethanol to thereby obtain a compound(XVIII-8).

Step 18-8

The compound (XVIII-8) is reacted with an appropriate base such asmethylamine in an appropriate solvent such as methanol, and then reactedwith di-t-butyl dicarbonate and an appropriate base such astriethylamine to thereby obtain a compound (XVIII-9).

Step 18-9

The compound (XVIII-9) is reacted with an appropriate reductant such aslithium aluminum hydride in an appropriate solvent such as THF, and thenreacted with propionaldehyde, an appropriate reductant such as sodiumcyanoborohydride, and an appropriate dehydrating agent such as trimethylorthoformate in an appropriate solvent such as methanol to therebyobtain a compound (XVIII-10).

Step 18-10

The compound (XVIII-10) is reacted in an appropriate solvent such asmethanol in the presence of an appropriate acid such as hydrochloricacid. Then, it is reacted with commercially available 2-imidazolecarboxaldehyde, an appropriate reductant such as sodium borohydride, andan appropriate dehydrating agent such as trimethyl orthoformate in anappropriate solvent such as methanol. Subsequently, the resultant wasreacted with commercially available 1-methyl-2-imidazole carboxaldehyde,an appropriate reductant such as sodium borohydride, an appropriatedehydrating agent, and appropriate acid catalyst such as acetic acid inan appropriate solvent such as methanol to thereby obtain a compound(XVIII-11) which is a compound represented by the general formula (1).

Step 18-11

A commercially available compound, 4-bromobutyronitrile is reacted withtriphenylphosphine in an appropriate solvent such as toluene to therebyobtain a compound (XVIII-12).

Step 18-12

The above compound (XVIII-6) is reacted with the compound (XVIII-12) andan appropriate base such as lithium diisopropylamide in an appropriatesolvent such as THF to thereby obtain a compound (XVIII-13).

Step 18-13

The compound (XVIII-13) is reacted with an appropriate base such asmethylamine in an appropriate solvent such as methanol, and then reactedwith di-t-butyl dicarbonate and an appropriate base such astriethylamine. Subsequently, under hydrogen atmosphere, the resultant isreacted with an appropriate catalyst such as palladium hydroxide in anappropriate solvent such as ethanol to thereby obtain a compound(XVIII-14).

Step 18-14

The compound (XVIII-14) is reacted with an appropriate reductant such aslithium aluminum hydride in an appropriate solvent such as THF, and thenreacted with propionaldehyde, an appropriate reductant such as sodiumcyanoborohydride, and an appropriate dehydrating agent such as trimethylorthoformate in an appropriate solvent such as methanol to therebyobtain a compound (XVIII-15).

Step 18-15

The compound (XVIII-15) is reacted in an appropriate solvent such asmethanol in the presence of an appropriate acid such as hydrochloricacid.

Then, the resultant is reacted with commercially available 2-imidazolecarboxaldehyde, an appropriate reductant such as sodium borohydride, andan appropriate dehydrating agent such as trimethyl orthoformate in anappropriate solvent such as methanol.

Subsequently, the resultant was reacted with commercially available1-methyl-2-imidazole carboxaldehyde, an appropriate reductant such assodium borohydride, an appropriate dehydrating agent, and appropriateacid catalyst such as acetic acid in an appropriate solvent such asmethanol to thereby obtain a compound (XVIII-16) which is a compoundrepresented by the general formula (1).

PRODUCTION METHOD EXAMPLE 19

The reaction process steps of Production Method Example 19 are shown inFIG. 19.

Step 19-1

A known compound (XIX-1) is reacted with N-bromosuccinimide, anappropriate radical generator such as azobisisobutyronitrile in anappropriate solvent such as carbon tetrachloride, and then reacted withpotassium phthalimide in an appropriate solvent such as DMF to therebyobtain a compound (XIX-2).

Step 19-2

The compound (XIX-2) is reacted with an appropriate base such asmethylamine in an appropriate solvent such as methanol, then reactedwith di-t-butyl dicarbonate and an appropriate base such astriethylamine. Subsequently, the resultant is reacted with anappropriate reductant such as lithium aluminum hydride in an appropriatesolvent such as THF to thereby obtain a compound (XIX-3).

Step 19-3

The compound (XIX-3) is reacted with an appropriate oxidant such asmanganese dioxide in an appropriate solvent such as chloroform, and thenreacted with methyl triphenylphosphoranylideneacetate in an appropriatesolvent such as THF to thereby obtain a compound (XIX-4).

Step 19-4

The compound (XIX-4) is reacted under a hydrogen atmosphere with anappropriate catalyst such as palladium-carbon in an appropriate solventsuch as a chloroform-methanol mixture solvent, and then reacted with anappropriate reductant such as lithium aluminum hydride in an appropriatesolvent such as THF to thereby obtain a compound (XIX-5).

Step 19-5

The compound (XIX-5) is reacted with an appropriate oxidant such asDess-Martin periodinane in an appropriate solvent such asdichloromethane. Then, the resultant is reacted with dipropylamine, anappropriate reductant such as sodium cyanoborohydride, and anappropriate dehydrating agent such as trimethyl orthoformate in anappropriate solvent such as methanol to thereby obtain a compound(XIX-6).

Step 19-6

The compound (XIX-6) is reacted with an appropriate acid catalyst suchas hydrochloric acid in an appropriate solvent such as dioxane, and thenreacted with commercially available 2-imidazole carboxaldehyde, anappropriate reductant such as sodium borohydride, and an appropriatedehydrating agent such as trimethyl orthoformate in an appropriatesolvent such as methanol to thereby obtain a compound (XIX-7).

Step 19-7

The compound (XIX-7) is reacted with commercially available1-methyl-2-imidazole carboxaldehyde, an appropriate reductant such assodium borohydride, an appropriate dehydrating agent, and an appropriateacid catalyst such as acetic acid in an appropriate solvent such asmethanol to thereby obtain a compound (XIX-8) which is a compoundrepresented by the general formula (1).

PRODUCTION METHOD EXAMPLE 20

The reaction process steps of Production Method Example 20 are shown inFIG. 20.

Step 20-1

A commercially available compound (XX-1) is reacted with an appropriatereductant such as lithium aluminum hydride in an appropriate solventsuch as THF to thereby obtain a compound (XX-2).

Step 20-2

The compound (XX-2) is reacted with t-butyldimethylsilyl chloride and anappropriate base such as imidazole in an appropriate solvent such as DMFto thereby obtain a compound (XX-3).

Step 20-3

The compound (XX-3) is reacted with an appropriate oxidant such asmanganese dioxide in an appropriate solvent such as chloroform tothereby obtain a compound (XX-4).

Step 20-4

The compound (XX-4) is reacted with methyltriphenylphosphoranylideneacetate in an appropriate solvent such as THF,to thereby obtain a compound (XX-5).

Step 20-5

The compound (XX-5) is reacted, under hydrogen atmosphere, with anappropriate catalyst such as palladium black in an appropriate solventsuch as benzene to thereby obtain a compound (XX-6).

Step 20-6

The compound (XX-6) is reacted with an appropriate reductant such aslithium aluminum hydride in an appropriate solvent such as THF tothereby obtain a compound (XX-7).

Step 20-7

The compound (XX-7) is reacted with an appropriate oxidant such asDess-Martin periodinane in an appropriate solvent such asdichloromethane, to thereby obtain a compound (XX-8).

Step 20-8

The compound (XX-8) is reacted with dipropylamine, an appropriatereductant such as sodium cyanoborohydride, and an appropriatedehydrating agent such as trimethyl orthoformate in an appropriatesolvent such as methanol to thereby obtain a compound (XX-9).

Step 20-9

The compound (XX-9) is reacted with an appropriate deprotecting agentsuch as tetrabutylammonium fluoride (hereinafter, referred to as TBAF)in an appropriate solvent such as THF to thereby obtain a compound(XX-10).

Step 20-10

The compound (XX-10) is reacted with phthalimide, an appropriatedehydrating agent such as triphenylphosphine and diethylazodicarboxylate in an appropriate solvent to thereby obtain a compound(XX-11).

Step 20-11

The compound (XX-11) is reacted with an appropriate base such asmethylamine in an appropriate solvent such as methanol to thereby obtaina compound (XX-12).

Step 20-12

The compound (XX-12) is reacted with commercially available 2-imidazolecarboxaldehyde, an appropriate reductant such as sodium borohydride, andan appropriate dehydrating agent such as trimethyl orthoformate in anappropriate solvent such as methanol. Then, the resultant is reactedwith commercially available 1-methyl-2-imidazole carboxaldehyde, anappropriate reductant such as sodium borohydride, and an appropriateacid catalyst such as acetic acid in an appropriate solvent such asmethanol to thereby obtain a compound (XX-13) which is a compoundrepresented by the general formula (1).

Step 20-13

Methoxymethyltriphenylphosphonium chloride is reacted with anappropriate base such as lithium diisopropylamide in an appropriatesolvent such as THF. Then, the resulting reaction mixture is added andreacted with the above compound (XX-8) to thereby obtain a compound(XX-14).

Step 20-14

The compound (XX-14) is reacted with an appropriate acid catalyst suchas acetic acid in an appropriate solvent such as methanol, and thenreacted with dipropylamine, an appropriate reductant such as sodiumcyanoborohydride, and an appropriate dehydrating agent such as trimethylorthoformate in an appropriate solvent such as methanol to therebyobtain a compound (XX-15).

Step 20-15

The compound (XX-15) is reacted with phthalimide and an appropriatedehydrating agent such as triphenylphosphine and diethylazodicarboxylate in an appropriate solvent to thereby obtain a compound(XX-16).

Step 20-16

The compound (XX-16) is reacted with an appropriate base such asmethylamine in an appropriate solvent such as methanol to thereby obtaina compound (XX-17).

Step 20-17

The compound (XX-17) is reacted with commercially available 2-imidazolecarboxaldehyde, an appropriate reductant such as sodium borohydride, andan appropriate dehydrating agent such as trimethyl orthoformate in anappropriate solvent such as methanol. Then, the resultant is reactedwith commercially available 1-methyl-2-imidazole carboxaldehyde and anappropriate reductant such as sodium borohydride, an appropriatedehydrating agent such as trimethyl orthoformate or an appropriate acidcatalyst such as acetic acid in an appropriate solvent such as methanolto thereby obtain a compound (XX-18) which is a compound represented bythe general formula (1).

PRODUCTION METHOD EXAMPLE 21

The reaction process steps of Production Method Example 21 are shown inFIG. 21.

Step 21-1

The above compound (XVII-1) is reacted with iodopropane in anappropriate solvent such as DMF in the presence of an appropriate basesuch as potassium carbonate to thereby obtain a compound (XXI-1).

Step 21-2

The compound (XXI-1) is reacted with 5-t-butoxycarbonylaminovalericacid, an appropriate condensing agent and catalyst such as WSCI and HOBtin an appropriate solvent such as DMF to thereby obtain a compound(XXI-2).

Step 21-3

The compound (XXI-2) is reacted in an appropriate solvent such asmethanol in the presence of an appropriate acid such as hydrochloricacid, and then reacted with propionaldehyde, an appropriate reductantsuch as sodium cyanoborohydride, and optionally an appropriatedehydrating agent such as trimethyl orthoformate in an appropriatesolvent such as methanol to thereby obtain a compound (XXI-3).

Step 21-4

The compound (XXI-3) is reacted with an appropriate reductant such aslithium aluminum hydride in an appropriate solvent such as THF tothereby obtain a compound (XXI-4).

Step 21-5

The compound (XXI-4) is reacted with phthalimide and an appropriatedehydrating agent such as triphenylphosphine and diethylazodicarboxylate in an appropriate solvent to thereby obtain a compound(XXI-5).

Step 21-6

The compound (XXI-5) is reacted with an appropriate base such asmethylamine in an appropriate solvent such as methanol to thereby obtaina compound (XXI-6).

Step 21-7

The compound (XXI-6) is reacted with commercially available 2-imidazolecarboxaldehyde, an appropriate reductant such as sodium borohydride, andan appropriate dehydrating agent such as trimethyl orthoformate in anappropriate solvent such as methanol to thereby obtain a compound(XXI-7) which is a compound represented by the general formula (1).

Step 21-8

The compound (XXI-6) is reacted with commercially available 2-imidazolecarboxaldehyde, an appropriate reductant such as sodium borohydride, anappropriate dehydrating agent such as trimethyl orthoformate in anappropriate solvent such as methanol. Then, the resultant is reactedwith commercially available 1-methyl-2-imidazole carboxaldehyde, anappropriate reductant such as sodium borohydride, and an appropriatedehydrating agent such as trimethyl orthoformate or an appropriate acidcatalyst such as acetic acid in an appropriate solvent such as methanolto thereby obtain a compound (XXI-8) which is a compound represented bythe general formula (1).

PRODUCTION METHOD EXAMPLE 22

The reaction process steps of Production Method Example 22 are shown inFIG. 22.

Step 22-1

A commercially available compound (XXII-1) is reacted witht-butyldiphenylsilyl chloride and an appropriate base such as imidazolein an appropriate solvent such as DMF to thereby obtain a compound(XXII-2).

Step 22-2

The compound (XXII-2) is reacted with an appropriate oxidant such asN-methyl-morpholine-N-oxide and tetrapropylammonium perruthenate in anappropriate solvent such as dichloromethane to thereby obtain a compound(XXII-3).

Step 22-3

The compound (XXII-3) is reacted with the compound (XXII-4) and anappropriate base such as lithium bistrimethylsilyl amide in anappropriate solvent such as THF. Then, the resultant is reacted withmethanesulfonyl chloride and an appropriate base such as triethylaminein an appropriate solvent such as DMF, and further reacted with anappropriate strong base such as DBU to thereby obtain a compound(XXII-5).

Step 22-4

The compound (XXII-5) is reacted with an appropriate reductant such asK-Selectride® in an appropriate solvent such as THF to thereby obtain acompound (XXII-6).

Step 22-5

The compound (XXII-6) is reacted with an appropriate reductant such assodium borohydride in an appropriate solvent such as methanol to therebyobtain a compound (XXII-7).

Step 22-6

The compound (XXII-7) is reacted with methoxymethyl chloride and anappropriate base such as sodium hydride in an appropriate solvent suchas DMF to thereby obtain a compound (XXII-8).

Step 22-7

The compound (XXII-8) is reacted with an appropriate deprotecting agentsuch as TBAF in an appropriate solvent such as THF. Then, the resultantis reacted with an appropriate oxidant such asN-methyl-morpholine-N-oxide and tetrapropylammonium perruthenate in anappropriate solvent such as dichloromethane to thereby obtain a compound(XXII-9).

Step 22-8

The compound (XXII-9) is reacted with dipropylamine and an appropriatereductant such as sodium triacetoxy borohydride in an appropriatesolvent such as dichloroethane to thereby obtain a compound (XXII-10).

Step 22-9

The compound (XXII-10) is reacted with an appropriate cyanide reagentsuch as zinc cyanide and an appropriate catalyst such astetrakistriphenylphosphine palladium in an appropriate solvent such asDMF to thereby obtain a compound (XXII-11).

Step 22-10

The compound (XXII-11) is reacted with an appropriate reductant such aslithium aluminum hydride in an appropriate solvent such as THF tothereby obtain a compound (XXII-12).

Step 22-11

The compound (XXII-12) is reacted with carbethoxyphthalimide and anappropriate base such as potassium carbonate in an appropriate solventsuch as DMF to thereby obtain a compound (XXII-13).

Step 22-12

The compound (XXII-13) is reacted with an appropriate acid catalyst suchas hydrochloric acid in an appropriate solvent such as amethanol/dioxane mixture to thereby obtain a compound (XXII-14).

Step 22-13

The compound (XXII-14) is reacted with an appropriate base such ashydrazine monohydrate in an appropriate solvent such as methanol tothereby obtain a compound (XXII-15).

Step 22-14

The compound (XXII-15) is reacted with commercially available2-imidazole carboxaldehyde, an appropriate reductant such as sodiumborohydride, and an appropriate dehydrating agent such as trimethylorthoformate in an appropriate solvent such as methanol to therebyobtain a compound (XXII-16).

Step 22-15

The compound (XXII-26) is reacted with commercially available1-methyl-2-imidazole carboxaldehyde, an appropriate reductant such assodium borohydride, an appropriate dehydrating agent, and an appropriateacid catalyst such as acetic acid in an appropriate solvent such asmethanol to thereby obtain a compound (XXII-17) which is a compoundrepresented by the general formula (1).

PRODUCTION METHOD EXAMPLE 23

The reaction process steps of Production Method Example 23 are shown inFIG. 23.

Step 23-1

A commercially available compound (XXIII-1) is reacted with1-iodopropane and an appropriate base such as sodium hydride in anappropriate solvent such as DMF to thereby obtain a compound (XXIII-2).

Step 23-2

The compound (XXIII-2) is reacted with an appropriate reductant such astin(II) chloride and sodium borohydride in an appropriate solvent suchas ethanol to thereby obtain a compound (XXIII-3).

Step 23-3

The compound (XXIII-3) is reacted with 5-t-butoxy carbonylaminovalericacid and an appropriate condensing agent and catalyst such as WSCI andHOBt in an appropriate solvent such as DMF to thereby obtain a compound(XXIII-4).

Step 23-4

The compound (XXIII-4) is reacted in an appropriate solvent such asmethanol in the presence of an appropriate acid such as hydrochloricacid. Then, the resultant is reacted with propionaldehyde, anappropriate reductant such as sodium cyanoborohydride, and anappropriate acid catalyst such as acetic acid in an appropriate solventsuch as methanol to thereby obtain a compound (XXIII-5).

Step 23-5

The compound (XXIII-5) is reacted with an appropriate reductant such aslithium aluminum hydride in an appropriate solvent such as THF. Then,the resultant is reacted with commercially available 2-imidazolecarboxaldehyde, an appropriate reductant such as sodium borohydride, andan appropriate dehydrating agent such as trimethyl orthoformate in anappropriate solvent such as methanol. Subsequently, the resultant isreacted with commercially available 1-methyl-2-imidazole carboxaldehyde,an appropriate reductant such as sodium borohydride, and an appropriatedehydrating agent such as trimethyl orthoformate or an appropriate acidcatalyst such as acetic acid in an appropriate solvent such as methanolto thereby obtain a compound (XXIII-6) which is a compound representedby the general formula (1).

PRODUCTION METHOD EXAMPLE 24

The reaction process steps of Production Method Example 24 are shown inFIG. 24.

Step 24-1

A commercially available compound (XXIV-1) is reacted with anappropriate condensing agent and catalyst such as WSCI and HOBt inmethanol to thereby obtain a compound (XXIV-2).

Step 24-2

The compound (XXIV-2) is reacted with N-bromosuccinimide (hereinafter,referred to as NBS) and an appropriate radical generator such asazobisisobutyronitrile in an appropriate solvent such as carbontetrachloride to thereby obtain a compound (XXIV-3).

Step 24-3

The compound (XXIV-3) is reacted with potassium phthalimide in anappropriate solvent such as DMF to thereby obtain a compound (XXIV-4).

Step 24-4

The compound (XXIV-4) is reacted with an appropriate base such ashydrazine monohydrate in an appropriate solvent such as methanol, andthen reacted with di-t-butyl dicarbonate and an appropriate base such astriethylamine to thereby obtain a compound (XXIV-5).

Step 24-5

The compound (XXIV-5) is reacted with an appropriate base such as sodiumhydroxide and water in an appropriate solvent such as methanol tothereby obtain a compound (XXIV-6).

Step 24-6

The compound (XXIV-6) is reacted with the above compound (IV-6) in anappropriate solvent such as xylene to thereby obtain a compound(XXIV-7).

Step 24-7

The compound (XXIV-7) is reacted in an appropriate solvent such asmethanol in the presence of an appropriate acid such as hydrochloricacid. Then, the resultant is reacted with commercially available2-imidazole carboxaldehyde, an appropriate reductant such as sodiumborohydride, and an appropriate dehydrating agent such as trimethylorthoformate in an appropriate solvent such as methanol to therebyobtain a compound (XXIV-8).

Step 24-8

The compound (XXIV-8) is reacted with commercially available1-methyl-2-imidazole carboxaldehyde, an appropriate reductant such assodium borohydride, an appropriate dehydrating agent, and an appropriateacid catalyst such as acetic acid in an appropriate solvent such asmethanol to thereby obtain a compound (XXIV-9) which is a compoundrepresented by the general formula (1).

The following compounds can be exemplified as the amine compounds of thepresent invention:

-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylamino-butyl)-benzamide    [Compound No. 1],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-diisobutylamino-butyl)-benzamide    [Compound No. 2],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-aminobutyl)-benzamide    [Compound No. 3],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-cyclohexylamino-butyl)-benzamide    [Compound No. 4],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-benzyloxycarbonylaminobutyl)-benzamide    [Compound No. 5],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(2-methoxy-benzylamino)-butyl]-benzamide    [Compound No. 6],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(2-dipropylamino-ethyl)-benzamide    [Compound No. 7],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(2-cyclohexylaminoethyl)-benzamide    [Compound No. 8],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(cyclohexylmethyl-amino)-butyl]-benzamide    [Compound No. 9],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(4-t-butyl-benzylamino)-butyl]-benzamide    [Compound No. 10],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(2-trifluoromethyl)-benzylamino-butyl]-benzamide    [Compound No. 11],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(2-trifluoromethoxy)-benzylamino-butyl]-benzamide    [Compound No. 12],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(4-methylsulfanyl-benzylamino)-butyl]-benzamide    [Compound No. 13],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-{4-[(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-benzamide    [Compound No. 14],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminophenyl)-benzamide    [Compound No. 15],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-{4-[bis(3-methyl-butyl)-amino]butyl}-benzamide    [Compound No. 16],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dimethylamino-butyl)-benzamide    [Compound No. 17],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-cycloheptylaminobutyl)-benzamide    [Compound No. 18],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide    [Compound No. 19],-   N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 20],-   N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(thiazol-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 21],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(3-dipropylaminopropyl)-benzamide    [Compound No. 22],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(3-dipropylamino-2,2-dimethylpropyl)-benzamide    [Compound No. 23],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminobutyl)-benzenesulfonamide    [Compound No. 24],-   N-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N′,    N′-dipropylbutane-1,4-diamine [Compound No. 25]-   N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 26],-   N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(1H-pyrazol-3-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 27],-   N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-((2R)-pyrrolidin-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 28],-   N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-((2S)-pyrrolidin-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 29],-   N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(4-methyl-1H-imidazol-5-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 30],-   (4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-(4-dipropylaminopiperidin-1-yl)-methanone    [Compound No. 31],-   (4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-(4-propylpiperazin-1-yl)-methanone    [Compound No. 32],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(3-dipropylaminomethylphenyl)-benzamide    [Compound No. 33],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-{[(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-benzamide    [Compound No. 34],-   [4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxy)-benzyl]-dipropylamine    [Compound No. 35],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-naphtalene-1-carboxylic    acid (4-dipropylaminomethylphenyl)-amide [Compound No. 36],-   (4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-[4-(1-propylbutyl)-piperazin-1-yl]-methanone    [Compound No. 37],-   (4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-(4-cyclohexylpiperazin-1-yl)-methanone    [Compound No. 38],-   (4-{[bis(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-(4-dipropylaminomethylphenyl)-amine    [Compound No. 39],-   4-{[bis(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminobutyl)-benzamide    [Compound No. 40],-   4-{[bis(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide    [Compound No. 41],-   [4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzylamino)-butyl]-carbamic    acid benzyl ester [Compound No. 42],-   (4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-(4-dipropylaminomethylphenyl)-amine    [Compound No. 43],-   (4-dipropylaminomethylphenyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-amine    [Compound No. 44],-   (4-dipropylaminomethylphenyl)-(4-{[(1H-imidazol-2-ylmethyl)-(2H-pyrazol-3-ylmethyl)-amino]-methyl}-benzyl)-amine    [Compound No. 45],-   N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2ylmethyl)-(6-methylpyridin-2-yl-methyl)-amino]-methyl}-benzamide    [Compound No. 46],-   N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(isoquinolin-3-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 47],-   N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 48],-   N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 49],-   N-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N-methyl-N′,N′-dipropylbutane-1,4-diamine    [Compound No. 50],-   N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(6-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 51],-   N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(6-bromopyridin-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 52],-   N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(3-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 53],-   N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(quinolin-4-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 54],-   N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(quinolin-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 55],-   N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 56],-   N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-3-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 57],-   N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-4-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 58],-   N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(3-ethoxypyridin-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 59],-   [4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxy)-butyl]-dipropylamine    [Compound No. 60],-   N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1H-benzimidazol-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 61],-   N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(2-methylthiazol-4-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 62],-   N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(isoquinolin-1-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 63],-   N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 64],-   4-({bis[1-(toluene-4-sulfonyl)-1H-imidazol-2-ylmethyl]-amino}-methyl)-N-(4-dipropylaminomethylphenyl)-benzamide    [Compound No. 65],-   4-{[bis(1-methanesulfonyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide    [Compound No. 66],-   2-({[4-(4-dipropylaminomethylphenylcarbamoyl)-benzyl]-(1-methyl-1H-imidazol-2-ylmethyl)-amino}-methyl)-imidazol-1-carboxylic    acid ethyl ester [Compound No. 67],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-N-methylbenzamide    [Compound No. 68],-   N-(4-dipropylaminomethylphenyl)-{[(1H-imidazol-2-ylmethyl)-(quinolin-3-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 70],-   N-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-4-dipropylaminomethylbenzamide    [Compound No. 71],-   N-(4-dipropylaminomethylphenyl)-4-{[(8-hydroxyquinolin-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 72],-   N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyrazine-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 73],-   N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyrazine-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 85],-   N-(4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyridine-2-ylmethyl)-amino]-methyl}-benzyl)-N′,N′-dipropylbutane-1,4-diamine    [Compound No. 75],-   N-(4-dipropylaminomethylphenyl)-4-{[(1-methyl-1H-imidazol-2-ylmethyl)-(5-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 76],-   4-{[bis(5-methylpyridin-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide    [Compound No. 77],-   N-(4-dipropylaminomethylphenyl)-4-{[N-(1H-imidazol-2-ylmethyl)-(4-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 78],-   {2-[4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxy)-phenyl]-ethyl}-dipropylamine    [Compound No. 79],-   [4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxymethyl)-benzyl]-dipropylamine    [Compound No. 80],-   N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-([1,2,3]-thiadiazole-4-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 81],-   4-{[(1-dimethylsulfamoyl-1H-imidazol-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide    [Compound No. 82],-   2-({[4-(4-dipropylaminomethylphenylcarbamoyl)-benzyl]-(1-methyl-1H-imidazol-2-ylmethyl)-amino}-methyl)-imidazol-1-carboxylic    acid dimethylamide [Compound No. 83],-   4-{[bis(1-dimethylsulfamoyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide    [Compound No. 84],-   N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-pyrazine-2-ylmethylamino]-methyl}-benzamide    [Compound No. 85],-   N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylisoxazol-3-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 86],-   4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzoyl)-(2-dipropylaminoethyl)-piperazine    [Compound No. 87],-   N-(4-cyclohexylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 88],-   4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-cyclohexylaminomethylphenyl)-benzamide    [Compound No. 89],-   N-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N′,N′-dipropylbutane-1,4-diamine    [Compound No. 90],-   N-(4-dipropylaminomethylphenyl)-4-{[(1-ethyl-1H-imidazol-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 91),-   N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-propyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 92],-   N-(4-dipropylaminomethylphenyl)-4-({(1H-imidazol-2-ylmethyl)-[1-(2-methoxymethoxyethyl)-1H-imidazol-2-ylmethyl]-amino}-methyl)-benzamide    [Compound No. 93],-   N-(4-dipropylaminomethylphenyl)-4-({[1-(2-hydroxyethyl)-1H-imidazol-2-ylmethyl]-(1H-imidazol-2-ylmethyl)-amino}-methyl)-benzamide    [Compound No. 94],-   4-{[bis(1-hexyloxycarbonyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide    [Compound No. 95],-   4-{[bis(1-heptyloxycarbonyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide    [Compound No. 96],-   4-{[bis(1-butoxycarbonyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide    [Compound No. 97],-   N-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N-methyl-N′,N′-dipropylbutane-1,4-diamine    [Compound No. 98],-   4-{[bis-(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(cyclohexyl-methyl-amino)-butyl]-benzamide    [Compound No. 99],-   N-[4-(cyclohexyl-methyl-amino)-butyl]-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 100],-   4-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethyl-phenyl)-benzamide    [Compound No. 101],-   N-(4-dipropylaminomethyl-phenyl)-4-{[(5-ethyl-pyridin-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 102],-   N-(4-cyclohexylamino-butyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzenesulfonamide    [Compound No. 103],-   N-cyclohexyl-N′-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N′-methyl-butane-1,4-diamine    [Compound No. 104],-   N-(4-dipropylamino-butyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzenesulfonamide    [Compound No. 105],-   N-(4-diisobutylamino-butyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzenesulfonamide    [Compound No. 106],-   4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-isobutylamino-butyl)-benzenesulfonamide    [Compound No. 107],-   4-{[bis-(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylamino-butyl)-N-methylbenzamide    [Compound No. 108],-   N-[4-(cyclohexyl-methyl-amino)-butyl]-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzenesulfonamide    [Compound No. 109],-   2-[(4-dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-amino]-ethanol    [Compound No. 110],-   4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-{4-[(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-benzenesulfonamide    [Compound No. 111],-   N-(4-dipropylamino-butyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-methylbenzamide    [Compound No. 112],-   N-(4-dipropylamino-butyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-methyl-benzenesulfonamide    [Compound No. 113],-   N-(4-di-n-propylaminomethyl-phenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1H-[1,2,4]-triazol-3-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 114],-   [4-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzimidazol-2-yl)-butyl]-dipropylamine    [Compound No. 115],-   N-(4-{[(imidazol-2-ylmethyl)-([1,2,4]-triazol-3-ylmethyl)-amino]-methyl}-benzyl)-N-methyl-N′,N′-dipropylbutane-1,4-diamine    [Compound No. 116],-   N-methyl-N-(4-{[(1-methyl-imidazol-2-ylmethyl)-([1,2,4]-triazol-3-ylmethyl)-amino]-methyl}-benzyl)-N′,N′-dipropyl-butane-1,4-diamine    [Compound No. 117],-   N-(4-dipropylaminomethylbenzyl)-N′-(1H-imidazol-2-ylmethyl)-N′-(1-methyl-1H-imidazol-2-ylmethyl)-1,4-butanediamine    [Compound No. 118],-   N-(4-dipropylaminomethylbenzyl)-N′-(1H-imidazol-2-ylmethyl)-N-methyl-N′-(1-methyl-1H-imidazol-2-ylmethyl)-butane-1,4-diamine    [Compound No. 119],-   [3-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-quinolin-2-yl)-propyl]-dipropylamine    [Compound No. 120],-   [3-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzo[b]-thiophen-2-yl)-propyl]-dipropyl-amine    [Compound No. 121],-   2-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-6-(3-dipropylaminopropyl)-naphtalene    [Compound No. 122],-   N-(4-di-n-propylaminomethyl-phenyl)-4-{[(1-methyl-imidazol-2-ylmethyl)-(1H-[1,2,4]-triazol-3-ylmethyl)-amino]-methyl}-benzamide    [Compound No. 123],-   [5-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-quinolin-2-yl)-pentyl]-dipropylamine    [Compound No. 124],-   2-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-6-(4-dipropylaminobutyl)-naphtalene    [Compound No. 125],-   [4-(6-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-1-propyl-1H-benzimidazol-2-yl)-butyl]-dipropylamine    [Compound No. 126],-   [4-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1-propyl-1H-benzimidazol-2-yl)-butyl]-dipropylamine    [Compound No. 127],-   [4-(5-{[(imidazol-2-ylmethyl)-(1-methylimidazol-2-ylmethyl)-amino]-methyl}-1-methoxy-indan-2-yl)-butyl]-dipropylamine    [Compound No. 128],-   [4-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1-propyl-1H-benzimidazol-2-yl)-butyl]-dipropylamine    [Compound No. 129],-   2-(4-di-n-propylamino-butyl)-5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-isoindole-1,3-dione    [Compound No. 130],-   N-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1H-imidazol-2-ylmethyl)-N-methyl-N′,N′-dipropyl-butane-1,4-diamine    [Compound No. 131],-   N-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-thiazol-2-ylmethyl)-N-methyl-N′,N′-dipropyl-butane-1,4-diamine    [Compound No. 132],-   5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-pyridin-2-carboxylic    acid (4-dipropylamino-butyl)-amide [Compound No. 133],-   5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-pyrazine-2-carboxylic    acid (4-dipropylamino-butyl)-amide [Compound No. 134],-   [3-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1H-indol-2-yl)-propyl]-dipropyl-amine    [Compound No. 135]-   2-(4-dipropylamino-butyl)-5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-indan-1-one    [Compound No. 136],-   2-(4-dipropylamino-butyl)-5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-inden-1-one    [Compound No. 137],-   3-amino-2-(4-dipropylamino-butyl)-5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-inden-1-one    [Compound No. 138],-   [4-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzothiazol-2-yl)-butyl]-dipropyl-amine    [Compound No. 139],-   [3-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1H-benzimidazol-2-ylsulfanyl)-propyl]-dipropyl-amine    [Compound No. 140],-   [3-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1H-inden-2-yl)-propyl]-dipropyl-amine    [Compound No. 141]-   [3-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzofuran-2-yl)-propyl]-dipropyl-amine    [Compound No. 142],-   2-(4-dipropylamino-butyl)-5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-2,3-dihydro-isoindol-1-one    [Compound No. 143],-   2-(4-dipropylamino-butyl)-6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1,1-dioxo-1,2-dihydro-1λ6-benzo[d]-isothiazol-3-one    [Compound No. 144],-   [4-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1,1-dioxo-1H-1(6-benzo[e]-[1,2]-thiazin-2-yl)-butyl]-dipropyl-amine    [Compound No. 145],-   2-(4-dipropylamino-butyl)-6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1,2-dihydro-indazol-3-one    [Compound No. 146],-   [4-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-3,4-dihydro-1H-isoquinolin-2-yl)-butyl]-dipropyl-amine    [Compound No. 147],-   [4-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-quinolin-2-yl)-butyl]-dipropyl-amine    [Compound No. 148],-   [4-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-quinoxalin-2-yl)-butyl]-dipropyl-amine    [Compound No. 149],-   3-(4-dipropylamino-butyl)-7-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-chromen-2-one    [Compound No. 150],-   (3-dipropylaminomethyl-phenyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-methanone    [Compound No. 151],-   3-(4-dipropylamino-butyl)-8-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-3,4-dihydro-1H-benzo[e]-[1,4]-diazepin-2,5-dione    [Compound No. 152],-   3-(4-dipropylamino-butyl)-7-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-3,4-dihydro-1H-benzo[e]-[1,4]-diazepin-2,5-dione    [Compound No. 153],-   2-(4-dipropylamino-butyl)-6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-3,4-dihydro-2H-isoquinolin-1-one    [Compound No. 154],-   N-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-thiophen-2-ylmethyl)-N-methyl-N′,N′-dipropyl-butane-1,4-diamine    [Compound No. 155],-   [4-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-quinazolin-2-yl)-butyl]-dipropyl-amine    [Compound No. 156],-   [4-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-chroman-2-yl)-butyl]-dipropyl-amine    [Compound No. 157],-   [4-(7-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-chroman-3-yl)-butyl]-dipropyl-amine    [Compound No. 158],-   3-(4-dipropylamino-butyl)-7-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-chromen-4-one    [Compound No. 159],-   2-(4-dipropylamino-butyl)-7-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-2,3-dihydro-1H-isoquinolin-4-one    [Compound No. 160],-   2-(4-dipropylamino-butyl)-7-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-2,3,4,5-tetrahydro-benzo[c]-azepin-1-one    [Compound No. 161],-   2-(4-dipropylamino-butyl)-7-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-2,5-dihydro-benzo[c]-azepin-1-one    [Compound No. 162],-   6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-4-oxo-3,4-dihydro-quinazolin-2-carboxylic    acid (2-dipropylamino-ethyl)-amide [Compound No. 163],-   2-dipropylamino-5-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-methyl-amino]-valeric    acid [Compound No. 164],-   5-dipropylamino-2-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-methyl-amino]-valeric    acid [Compound No. 165],-   [4-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1H-inden-2-yl)-butyl]-dipropylamine    [Compound No. 166],-   [4-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1H-indol-2-yl)-butyl]-dipropylamine    [Compound No. 167],-   [4-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1-methyl-1H-indol-2-yl)-butyl]-dipropylamine    [Compound No. 168],-   [4-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzofuran-2-yl)-butyl]-dipropylamine    [Compound No. 169],-   [4-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzoxazol-2-yl)-butyl]-dipropylamine    [Compound No. 170],-   [4-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzothiazol-2-yl)-butyl]-dipropylamine    [Compound No. 171],

The present invention relates to a CXCR4 antagonist including theabove-described compounds or a pharmacologically acceptable salt thereofas an active ingredient.

The CXCR4 antagonist or salt thereof according to the present inventionmay be used in treatment or prevention of viral disease such as AIDS,cancer treatment, or treatment or prevention of rheumatism, etc.

The pharmacologically acceptable salt is a salt which may be formed bythe amine compound represented by the above described formula (1), andmay be any salt that is pharmacologically acceptable. For example,trifluoroacetates, hydrochloric acid saltshydrochlorides, acetates,sulfuric acid salts, nitric acid salts, lactic acid salts, maleic acidsalts, methanesulfonic acid salts, toluenesulfonic acid salts, tartaricacid salts, citric acid salts, oxalic acid salts, malonic acid salts,fumaric acid salts, propionic acid salts, butanoic acid saltssulfates,nitrates, lactates, maleates, methane sulfonates, toluene sulfonates,tartrates, citrates, oxalates, malonates, succinates, fumarates,propionates, butyrates, glucuronates, terephthalates, phosphorates, andthe like can be given. Those compounds may form a hydrate or a solvate.

One or two or more asymmetric carbon atoms may exist in the compoundrepresented by the general formula (1); when one asymmetric carbon atomsexists, the compound may be in any form of a pure optically-activesubstance represented as absolute configuration of R or S, a mixturethereof in an arbitrary ratio, and a racemic mixture thereof, and whentwo or more asymmetric carbon atoms exist in the compound, the compoundmay be in any form of an optically pure diastereomer, a racemic mixturethereof, and a combination thereof in an arbitrary ratio.

The medical preparation including the compound of the present inventionrepresented by the general formula (1) or pharmacologically acceptablesalt thereof as an active ingredient may be administered orally orparenterally in a form of tablet, powder, granule, capsule, pill,suppository, injection, eye-drops, solution, troche, aerosol,suspension, emulsion, syrup, or the like, mixed with a well-knownpharmacologically acceptable carrier, excipient, diluent, extender,decaying agent, stabilizer, preservative, buffer, emulsifier, perfumingagent, colorant, sweetener, thickening agent, flavor, solubilizingagent, and other additives, specific examples thereof including: water;vegetable oil; alcohol such as ethanol or benzyl alcohol; carbohydratesuch as glycol, glycerol triacetate, gelatin, lactose, or starch;magnesium stearate; potassium stearate; tarc; lanoline; vaseline;macrogol; crystalline cellulose; hydroxypropyl cellulose, and the like.While the dose may vary depending on the kind and degree of disease, thekind of the compound to be administered, the administration path, andthe age, sex, and weight of the patient, in general, 0.1 to 5,000 mg),particularly 1 to 3,000 mg) per one adult is preferably administered. Inthe case of a prodrug, it is preferable to administer 1 to 5,000 mg) peradult.

EXAMPLES

A production method of CXCR4 antagonist of the present invention willnow be described in more detail with reference to Examples. Hereinafter,unless particularly described, reagents used are commercially availableproducts (e.g., Tokyo Kasei Kogyo Co. Ltd. (Tokyo), KANTO KAGAKU(Tokyo), etc.) readily available to a person skilled in the art.

EXAMPLES Production Example 1 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylamino-butyl)-benzamide[Compound No. 1] Example 1-1 Synthesis of4-[N-Boc-N-(1H-imidazol-2-ylmethyl)aminomethyl]-benzoic acid

Commercially available methyl bromomethylbenzoate (manufactured byAldrich Corporation) (10.0 g) was dissolved in DMF (100 ml), and thesolution was added with potassium phthalimide potassium salt(manufactured by Tokyo Kasei Kogyo Co., Ltd.) (9.70 g) and stirred atroom temperature for 1.5 hours. After completion of the reaction, thesolution was concentrated, and water was added to the concentrate. Then,extraction was performed with chloroform. The resultant solution waswashed with saturated saline solution and dried with anhydrous sodiumsulfate, and the solvent was distilled off, thereby obtaining a whitesolid (12.9 g). Subsequently, 7.56 g of the solid was dissolved inmethanol (100 ml), and the solution was added with hydrazine monohydrate(manufactured by Nacalai Tesque, Inc.) (6.25 ml) and stirred at 60(C for1.5 hours. After completion of the reaction, the precipitated solid wasseparated by filtration, and the solvent was distilled off. Water wasadded to the residue, and extraction was performed with chloroform. Theresultant solution was washed with a 0.3 mol/l sodium hydroxide aqueoussolution and saturated saline solution and dried with anhydrous sodiumsulfate, and the solvent was distilled off. Methanol (120 ml) and2-imidazole carboxaldehyde (manufactured by Aldrich Corporation) (2.35g) were added to the residue, followed by stirring at room temperaturefor 2 days. After completion of the reaction, the precipitated solid wasseparated by filtration. The liquid layer was evaporated to dryness, andwashing was performed by adding anhydrous methanol (30 ml). Then, thesolid was separated by filtration. The resultant solid and the solidthat had been previously separated by filtration were suspended inmethanol (86 ml), and sodium borohydride (1.42 g) was added underice-cooling. The solution was stirred at room temperature for 1 hour,and the solvent was distilled off. After addition of water, extractionwas performed with chloroform, and the organic layer was washed withsaturated saline solution and dried with anhydrous sodium sulfate,followed by concentration under reduced pressure and drying, therebyobtaining a colorless viscous liquid (4.32 g). 4.28 g of the liquid wasdissolved in DMF (65 ml), and the solution was added with di-t-butyldicarbonate (8.90 ml) and stirred at room temperature for 1 hour. Aftercompletion of the reaction, the solvent was distilled off, and theresidue was dissolved in chloroform, followed by washing with saturatedsaline solution. After drying with anhydrous sodium sulfate, the solventwas distilled off, and THF (43 ml), methanol (43 ml), and a 1 mol/lsodium hydroxide aqueous solution (43 ml) were added to the residue,followed by stirring at room temperature for 14 hours. After completionof the reaction, the solvent was distilled off, and water (5 ml) wasadded to the residue. Further, a 1 mol/l hydrochloric acid aqueoussolution was carefully added to the solution, and the acid-precipitatewas separated by filtration and dried, thereby obtaining the subjectcompound (4.87 g) as a white solid.

MS(FAB, Pos.): m/z=332[M+H]⁺

Example 1-2 Synthesis of N,N-dipropylbutane-1,4-diamine

N-(4-aminobutyl)carbamic acid t-butyl ester (manufactured by Tokyo KaseiKogyo Co., Ltd.) (500 ml) was dissolved in methanol (10 ml) and thenadded with propionaldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.)(0.418 ml), sodium cyanoborohydride (404 mg), and trimethyl orthoformate(1.60 g), followed by stirring at room temperature for 12 hours. Aftercompletion of the reaction, the solvent was distilled off. Then, theresidue was added with chloroform, washed with distilled water andsaturated saline solution, and then dried with anhydrous sodium sulfate.After concentration and evaporation to dryness, methanol (4.0 ml) and a4 mol/l hydrogen chloride/dioxane solution (4.0 ml) were added to thedried product and the whole was stirred at room temperature for 2 hours.After completion of the reaction, the solvent was distilled off and thendioxane was added to wash the residue, thereby obtaining hydrochloride(654 mg) of the subject compound.

MS(FAB, Pos.): m/z=173[M+H]⁺

Example 1-3 Synthesis of4-{[N-Boc-N-(1H-imidazol-2-ylmethyl)amino]methyl}-N-(4-dipropylaminobutyl)benzamide

The compound (203 mg) obtained in Example 1-2 was dissolved in DMF (5.0ml) and chloroform (5.0 ml), and then added with triethylamine (0.374ml), WSCI hydrochloride (382 mg), HOBt (200 mg), and the compound (463mg) obtained in Example 1-1 and the whole was stirred at roomtemperature for 23 hours. After completion of the reaction, the solventwas distilled off. Then, the residue was added with chloroform andwashed with water and saturated saline solution. The solution was driedwith anhydrous sodium sulfate and then the solvent was distilled off.Subsequently, the residue was purified through silica gel columnchromatography (chloroform/methanol/water), thereby obtaining thesubject compound (168 mg) as colorless foam.

MS(FAB, Pos.): m/z=486[M+H]⁺

Example 1-4 Synthesis of4-{[N-(1H-imidazol-2-ylmethyl)amino]methyl-N-(4-dipropylaminobutyl)benzamide

The compound (117 mg) obtained in Example 1-3 was dissolved in methanol(1.2 ml) and then added with a 4 mol/l hydrogen chloride/dioxanesolution (1.2 ml), followed by stirring at room temperature for 5 hours.After completion of the reaction, the solvent was distilled off. Then,the residue was dissolved in water and then purified through solid-phaseextraction column (Sep-Pak®, tC18, manufactured by Waters Corporation),thereby obtaining hydrochloride (118 mg) of the subject compound as awhite solid.

MS(FAB, Pos.): m/z=386[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.89(6H, t, J=7.3 Hz), 1.54–1.62(2H, m),1.61–1.83(6H, m), 2.93–3.01(4H, m), 3.00–3.01(2H, m), 3.30(2H, dd,J=6.1, 12.3 Hz), 4.37(2H, s), 4.52(2H, s), 7.62–7.64(4H, m), 7.92(2H, d,J=8.1 Hz), 8.71(1H, d, J=4.4 Hz).

Example 1-5 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylamino-butyl)-benzamide[Compound No. 1]

The compound (24.0 mg) obtained in Example 1-4 was suspended inchloroform and extracted by the addition of a 1 mol/l sodium hydroxideaqueous solution. The organic layer was dried with anhydrous sodiumsulfate. After the solvent had been distilled off, the residue wasdissolved in methanol (0.5 ml) and added with 2-imidazole carboxaldehyde(4.60 mg) and sodium cyanoborohydride (4.60 mg). Then, the solution wasadjusted to pH 5 with acetic acid and stirred at room temperature for 19hours. After completion of the reaction, the solvent was distilled offand the residue was then suspended in chloroform, followed by washingwith a 1 mol/l sodium hydroxide aqueous solution and saturated salinesolution. Subsequently, the residue was dried with anhydrous sodiumsulfate and the solvent was then distilled off. The residue wasdissolved in chloroform and added with methanesulfonic acid (12.6 μl).The solvent was distilled off and the residue was then purified throughsilica gel column chromatography (chloroform/methanol/water), therebyobtaining methanesulfonate (21.9 mg) of the subject compound as a whitesolid.

MS(FAB, Pos.): m/z=486[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.89(6H, t, J=7.3 Hz), 1.50–1.69(8H, m),2.94–3.01(4H, m), 3.04–3.13(2H, m), 3.24–3.32(2H, m), 3.75(2H, s),4.08(4H, s), 7.43(2H, d, J=8.4 Hz), 7.62(4H, s), 7.77(2H, d, J=8.4 Hz),8.51(1H, t, J=5.8 Hz), 8.99(1H, brs).

Production Example 2 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-diisobutylamino-butyl)-benzamide[Compound No. 2] Example 2-1 Synthesis of4-(1H-imidazol-2-ylmethylaminomethyl) benzoic acid methyl ester

The compound (2.01 g) obtained in Example 1-1 was dissolved in asolution (20 ml) of 10% hydrogen chloride/methanol and the solution wasthen stirred at room temperature for 23 hours. After completion of thereaction, the solution was concentrated and suspended in chloroform.Then, the suspension was added with a 1 mol/l sodium hydroxide aqueoussolution to separate the solution into layers. The organic layer wasdried with anhydrous sodium sulfate and the solvent was then distilledoff. The residue was dried under reduced pressure, thereby obtaining thesubject compound (0.80 g) as a white solid.

MS(FAB, Pos.): m/z=246[M+H]⁺

Example 2-2 Synthesis of4-[N,N-bis-(imidazol-2-ylmethyl)aminomethyl]-benzoic acid

The compound (800 mg) synthesized in Example 2-1 was dissolved inmethanol (32 ml) and then the solution was added with 2-imidazolecarboxaldehyde (345 mg) and sodium cyanoborohydride (307 mg). Then, thesolution was adjusted to approximately pH 5 with acetic acid and stirredat room temperature for 16 hours. After completion of the reaction, thesolvent was distilled off and the residue was then suspended inchloroform, followed by washing with a 1 mol/l sodium hydroxide aqueoussolution and saturated saline solution. Subsequently, the resultant wasdried with anhydrous sodium sulfate and the solvent was then distilledoff. The residue was dissolved in methanol (10 ml) and a 1 mol/l sodiumhydroxide aqueous solution (10 ml), followed by stirring at roomtemperature for 2.5 hours. After completion of the reaction, the organicsolvent portion was distilled off. Then, the residue was adjusted to pH6 by the addition of 1 mol/l hydrochloric acid. The aqueous layer waswashed with chloroform. The solution was concentrated to remove waterand the residue was then added with methanol. After the insoluble matterhad been removed through filtration, the methanol was distilled off andthe residue was then concentrated under reduced pressure, therebyobtaining the subject compound (1.05 g).

MS(FAB, Pos.): m/z=312[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=3.70(2H, s), 3.90(4H, s), 7.32(4H, s),7.52(2H, d, J=8.2 Hz), 7.86(2H, d, J=8.2 Hz).

Example 2-3 Synthesis of N-benzyloxycarbonyl-N′,N′-1,4-diaminobutane

N-benzyloxycarbonyl-1,4-diaminobutane (200 mg) synthesized by the methoddescribed in Chemical Pharmaceutical Bulletin (Chem. Pharm. Bull) vol.32, page 3428 (1984) was dissolved in methanol (6.0 ml) and added withdi-isobutyl aldehyde (197 μl) and sodium cyanoborohydride (136 mg).Then, the solution was adjusted to approximately pH 5 with acetic acidand stirred at room temperature for 14 hours. After completion of thereaction, the solvent was distilled off and the residue was thensuspended in chloroform, followed by washing with a 1 mol/l sodiumhydroxide aqueous solution and saturated saline solution. The resultantwas dried with anhydrous sodium sulfate and the solvent was thendistilled off. Subsequently, the residue was purified through silica gelcolumn chromatography (chloroform/methanol), thereby obtaining thesubject compound (125 mg) as a colorless liquid.

MS(FAB, Pos.): m/z=335[M+H]⁺

Example 2-4 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-diisobutylamino-butyl)-benzamide[Compound No. 2]

The compound (125 mg) obtained in Example 2-3 was dissolved in ethanol(7.5 ml). Then, the solution was added with 10% palladium-carbon (63.0mg), followed by stirring under a hydrogen atmosphere at roomtemperature for 1 hour. After completion of the reaction, the catalystwas removed by Celite filtration and the solvent was then distilled off,followed by distilling azeotropically with dichloromethane to obtain adeprotected product. Subsequently, the product was dissolved in DMF (3.5ml) and added with DCC (84.9 mg), HOBt (55.6 mg), and the compound (128mg) obtained in Example 2-2, followed by stirring at room temperaturefor 17 hours. After completion of the reaction, insoluble matter wasremoved by decantation and the solvent was then distilled off. Theresidue was dissolved in chloroform and washed with a 1 mol/l sodiumhydroxide aqueous solution. After the organic layer was added withhydrochloric acid, the solution was separated into layers. Then, theaqueous layer was adjusted to pH 11 by the addition of a sodiumhydroxide aqueous solution, followed by extraction with chloroform.Subsequently, the organic layer was dried and concentrated withanhydrous sodium sulfate. The residue was purified through silica gelcolumn chromatography (chloroform/methanol/water) and treated withhydrochloric acid, thereby obtaining hydrochloride (54.5 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=494[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.96(6H, d, J=6.8 Hz), 0.98(6H, d, J=6.8Hz), 1.51–1.69(2H, m), 1.67–1.75(2H, m), 2.05(2H, sept., J=6.8 Hz),2.82–2.96(4H, m), 3.08–3.13(2H, m), 3.25–3.33(2H, m), 3.71(2H, s),4.13(4H, s), 7.54(2H, d, J=8.1 Hz), 7.61(4H, s), 7.78(2H, d, J=8.1 Hz),8.59(1H, brs), 8.97(1H, br).

Production Example 3 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-aminobutyl)-benzamide[Compound No. 3] Example 3-1 Synthesis of4-{N,N-bis-(imidazol-2-ylmethyl)amino]methyl}-N-(Boc-aminobutyl)-benzamide

The compound (406 mg) obtained in Example 2-2 andN-(4-aminobutyl)carbamic acid t-butyl ester (Tokyo Kasei Kogyo Co.,Ltd.) (206 mg) were dissolved in DMF (12 ml) and added with WSCIhydrochloride (410 mg), followed by stirring for 6.5 hours. Aftercompletion of the reaction, the solvent was distilled off and theresidue was then dissolved in chloroform. After that, the solution waswashed with a 1 mol/l sodium hydroxide aqueous solution and saturatedsaline solution and then concentrated. The residue was purified throughsilica gel column chromatography (chloroform/methanol), therebyobtaining the subject compound (23.0 mg) as colorless foam.

MS(FAB, Pos.): m/z=482[M+H]⁺

Example 3-2 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-aminobutyl)-benzamide[Compound No. 3]

The compound (22.0 mg) obtained in Example 3-1 was dissolved in methanol(0.2 ml) and added with a 4 mol/l hydrogen chloride/dioxane solution(0.22 ml), followed by stirring at room temperature for 30 minutes.After completion of the reaction, the solvent was distilled off. Theresidue was dried under reduced pressure and then suspended inchloroform. The suspension was washed with a 1 mol/l sodium hydroxideaqueous solution and saturated saline solution and dried with anhydroussodium sulfate. Subsequently, the solvent was distilled off and theresidue was then dried under reduced pressure, thereby obtaining thesubject compound (32.5 mg).

MS(FAB, Pos.): m/z=382[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=2.73–2.81(2H, m), 3.24–3.30(2H, m), 3.71(2H,s), 4.14(4H, s), 7.53(2H, d, J=8.2 Hz), 7.60(4H, s), 7.67(2H, d, J=8.2Hz), 7.93(3H, brs), 8.59(1H, t, J=5.6 Hz), 14.8(3H, brs).

Production Example 44-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-cyclohexylamino-butyl)-benzamide[Compound No. 4] Example 4-1 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-cyclohexylamino-butyl)-benzamide[Compound No. 4]

The compound (28.8 mg) obtained in Example 3-2 was dissolved in methanol(0.5 ml). The solution was added with cyclohexanone (8.80 μl) and sodiumcyanoborohydride (4.40 mg) and then adjusted to approximately pH 5 withacetic acid, followed by stirring at room temperature for 16 hours.After completion of the reaction, the solvent was distilled off. Then,the residue was dissolved in chloroform and washed with a 1 mol/l sodiumhydroxide aqueous solution and saturated saline solution, followed bythe addition of 1 mol/l hydrochloric acid to extract the objectivesubstance. Subsequently, the aqueous layer was concentrated underreduced pressure and then the residue was purified through a solid-phaseextraction column (Bond Elut® C18 (manufactured by Varian Inc.), 200mg), thereby obtaining hydrochloride (17.6 mg) of the subject compoundas a white solid.

MS(FAB, Pos.): m/z=463[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=1.03–1.14(1H, m), 1.16–1.33(4H, m),1.54–1.69(5H, m), 1.70–1.80(2H, m), 1.98–2.06(2H, m), 2.85–2.97(3H, m),3.23–3.31(2H, m), 3.69(2H, s), 4.11(4H, s), 7.45(2H, d, J=8.4 Hz),7.58(4H, s), 7.76(2H, d, J=8.4 Hz), 8.48(1H, brs), 8.72(1H, br).

Production Example 5 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-benzyloxycarbonylaminobutyl)-benzamide[Compound No. 5] Example 5-1 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-benzyloxycarbonylaminobutyl)-benzamide[Compound No. 5]

The compound (413 mg) obtained in Example 2-2 andN-benzyloxycarbonyl-1,4-diaminobutane (247 mg) were dissolved inanhydrous DMF (8.0 ml) and added with WSCI hydrochloride (234 mg) andHOBt (165 mg), followed by stirring at room temperature for 14 hours.After completion of the reaction, the solvent was distilled off. Theresidue was dissolved in chloroform, washed with 1 mol/l hydrochloricacid, a 1 mol/l sodium hydroxide aqueous solution, and saturated salinesolution, and dried with anhydrous magnesium sulfate, followed bydistilling the solvent off. Subsequently, the residue was purifiedthrough silica gel column chromatography (chloroform/methanol/water) andtreated with hydrochloric acid, thereby obtaining hydrochloride (23.0mg) of the subject compound as a white solid.

MS(FAB, Pos.): m/z=516[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=1.40–1.50(4H, m), 2.99(2H, dd, J=6.3, 12.4Hz), 3.22(2H, dd, J=6.1, 12.6 Hz), 3.71(2H, s), 4.12(4H, s), 4.99(2H,s), 7.27–7.37(6H, m), 7.50(2H, d, J=8.3 Hz), 7.61(4H, s), 7.76(2H, dd,J=8.3 Hz), 8.44(1H, t, J=5.6 Hz).

Production Example 6 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(2-methoxy-benzylamino)-butyl]-benzamide[Compound No. 6] Example 6-1 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(2-methoxy-benzylamino)-butyl]-benzamide[Compound No. 6]

The compound (63.9 mg) obtained in Example 3-2 was dissolved inanhydrous methanol (1.3 ml) and then added with 2-methoxybenzaldehyde(manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.0350 ml) and trimethylorthoformate (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.0560 ml),followed by stirring at room temperature for 30 minutes. The solutionwas added with sodium borohydride (19.3 mg), followed by stirring atroom temperature for 15 minutes. After completion of the reaction, thesolvent was distilled off. Then, the residue was added with water andextracted with chloroform, and the extract was washed with saturatedsaline solution, followed by drying with anhydrous magnesium sulfate.The solvent was distilled off and treated with hydrochloric acid. Theresidue was purified through a solid-phase extraction column (Sep-Pack®,tC18, manufactured by Waters Corporation), thereby obtaininghydrochloride (6.80 mg) of the subject compound as a white solid.

MS(FAB, Pos.): m/z=502[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=1.53–1.57(2H, m), 1.64–1.69(2H, m), 2.92(2H,br), 3.25(2H, dd, J=6.7, 12.5 Hz), 3.71(2H, s), 3.83(2H, s),4.06–4.08(2H, m), 4.10(4H, s), 6.99(1H, dt, J=1.1, 7.5 Hz), 7.09(1H, d,J=7.6 Hz), 7.40–7.46(2H, m), 7.52(2H, d, J=8.4 Hz), 7.60(4H, s),7.77(2H, d, J=8.4 Hz), 8.53(1H, t, J=5.5 Hz), 8.81(2H, br).

Production Example 7 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(2-dipropylamino-ethyl)-benzamide[Compound No. 7] Example 7-1 Synthesis of mono-N-Boc-ethylenediamine

Ethylenediamine (manufactured by Kanto Kagaku) (5.01 g) was dissolved inchloroform (100 ml) and added with triethylamine (13.9 ml), followed bydropping a chloroform solution (5.0 ml) of di-t-butyl dicarbonate (2.27g) therein. After the mixture had been stirred at room temperature for 4hours, the solvent was distilled off under reduced pressure and theresidue was then dissolved in ethyl acetate. Then, the residue waswashed with a 1 mol/l sodium hydroxide aqueous solution and water andextracted with ethyl acetate, and the extract was washed with saturatedsaline solution, followed by drying with anhydrous sodium sulfate. Afterfiltration, the solvent was distilled off under reduced pressure and theresidue was then purified through silica gel column chromatography(chloroform/methanol/water), thereby obtaining the subject compound(1.09 g) as a pale-yellow liquid.

MS(FAB, Pos.): m/z=161[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=1.37(9H, s), 2.49–2.54(2H, m), 2.90(2H, q,J=6.1 Hz), 6.74(1H, brs).

Example 7-2 Synthesis of4-{[bis-(1H-imidazol-2-ylmethyl)amino]methyl}-N-(2-N-Boc-aminoethyl)-benzamide

The compound (342 mg) obtained in Example 2-2, DCC (227 mg), and HOBt(149 mg) were dissolved in DMF (3.0 ml), followed by stirring for 10minutes. A DMF solution (2.0 ml) of the compound (160 mg) obtained inExample 7-1 was dropped in this solution, and the whole was stirred atroom temperature for 14 hours. After completion of the reaction, thesolvent was distilled off under reduced pressure. The residue wasdissolved in 0.2 mol/l hydrochloric acid and washed with chloroform. Theaqueous layer was added with a 1 mol/l sodium hydroxide aqueous solutionand extracted with chloroform. The organic layer was washed withsaturated saline solution, followed by drying with anhydrous sodiumsulfate. After filtration, the solvent was distilled off under reducedpressure and the residue was then purified through silica gel columnchromatography (chloroform/methanol), thereby obtaining the subjectcompound (334 mg) as a pale-yellow solid.

MS(FAB, Pos.): m/z=454[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=1.37(9H, s), 3.09(2H, q, J=6.3 Hz), 3.28(2H,q, J=6.3 Hz), 3.56(2H, s), 3.58(4H, s), 6.90–6.92(2H, m), 7.06(2H, br),7.48(2H, d, J=8.2 Hz), 7.78(2H, d, J=8.1 Hz), 8.41(1H, t, J=5.4 Hz).

Example 7-3 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(2-dipropylamino-ethyl)-benzamide[Compound No. 7]

The compound (165 mg) obtained in Example 7-2 was dissolved in methanol(1.7 ml). A 4 mol/l hydrogen chloride/dioxane solution (0.83 ml) wasadded in this solution, and the whole was stirred at room temperaturefor 1 hour. After completion of the reaction, the solvent was distilledoff under reduced pressure and the residue was dried under vacuum. Thedried product was dissolved in methanol (4.0 ml) and then added withtrimethyl orthoformate (165 μl), acetic acid (200 μl), propionaldehyde(78.0 μl), and sodium cyanoborohydride (68.6 mg) and stirred at roomtemperature for 23 hours. The solvent was distilled off under reducedpressure. Then, the residue was dissolved in chloroform and washed witha 1 mol/l sodium hydroxide aqueous solution, and added with 1 mol/lhydrochloric acid to transfer the objective substance to the aqueouslayer, followed by washing with chloroform. The 1 mol/l sodium hydroxideaqueous solution was added again to alkalinize the solution. Thesolution was subjected to extraction with chloroform and the extract wasthen washed with saturated saline solution and dried with anhydroussodium sulfate. After filtration, the solvent was distilled off underreduced pressure. Then, the residue was dried under vacuum and treatedwith hydrochloric acid, thereby obtaining hydrochloride (110 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=438[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.89(6H, t, J=7.3 Hz), 1.69(4H, sext., J=7.3Hz), 3.04–3.08(4H, m), 3.23(2H, m), 3.49–3.66(2H, m), 3.72(2H, s),4.14(4H, s), 7.54(2H, d, J=8.4 Hz), 7.60(4H, s), 7.83(2H, d, J=8.2 Hz),8.97(1H, brs), 10.40(1H, br).

Production Example 8 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(2-cyclohexylaminoethyl)-benzamide[Compound No. 8] Example 8-1 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(2-cyclohexylaminoethyl)-benzamide[Compound No. 8]

The compound (165 mg) obtained in Example 7-2 was dissolved in methanol(1.7 ml). A 4 mol/l hydrogen chloride/dioxane solution (0.83 ml) wasadded in this solution, and the whole was stirred at room temperaturefor 1 hour. After completion of the reaction, the solvent was distilledoff under reduced pressure and the residue was dried under vacuum,thereby obtaining a crude product. The product was dissolved in methanol(4.0 ml) and then added with trimethyl orthoformate (165 μl), aceticacid (200 μl), cyclohexanone (75.0 μl), and sodium cyanoborohydride(68.6 mg) and stirred for 23 hours at room temperature. The solvent wasdistilled off under reduced pressure. Then, the residue was dissolved inchloroform and washed with a 1 mol/l sodium hydroxide aqueous solution,and added with 1 mol/l hydrochloric acid to transfer the objectivesubstance to the aqueous layer, followed by washing with chloroform. The1 mol/l sodium hydroxide aqueous solution was added again to alkalinizethe solution. The solution was subjected to extraction with chloroformand the extract was then washed with saturated saline solution and driedwith anhydrous sodium sulfate. After filtration, the solvent wasdistilled off under reduced pressure. Then, the residue was dried undervacuum and treated with hydrochloric acid, thereby obtaininghydrochloride (116.0 mg) of the subject compound as a white solid.

MS(FAB, Pos.) m/z=436[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=1.08–1.35(6H, m), 1.59(2H, d, J=12.7 Hz),1.75(2H, d, J=12.7 Hz), 2.04(2H, d, J=10.2 Hz), 3.00–3.09(3H, m),3.59(2H, q, J=5.9 Hz), 3.72(2H, s), 4.14(4H, s), 7.53(2H, d, J=8.2 Hz),7.61(4H, s), 7.86(2H, d, J=8.4 Hz), 8.90(1H, t, J=5.9 Hz), 9.07(1H,brs).

Production Example 9 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(cyclohexylmethyl-amino)-butyl]-benzamide[Compound No. 9] Example 9-1 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(cyclohexylmethyl-amino)-butyl]-benzamide[Compound No. 9]

The compound (50.6 mg) obtained in Example 3-2 was dissolved inanhydrous methanol (2.0 ml) and added with cyclohexane carboxaldehyde(manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.0240 ml) and trimethylorthoformate (0.0430 ml), followed by stirring at room temperature for30 minutes. Then, the solution was added with sodium borohydride (14.8mg), followed by stirring at room temperature for 15 minutes. Aftercompletion of the reaction, the solvent was distilled off. The residuewas dissolved in chloroform and washed with a 1 mol/l sodium hydroxideaqueous solution and saturated saline solution, followed by drying withanhydrous magnesium sulfate. The solvent was distilled off and theresidue was then treated with hydrochloric acid. Subsequently, theresidue was purified through silica gel column chromatography(chloroform/methanol/water), thereby obtaining hydrochloride (42.0 mg)of the subject compound as a white solid.

MS(FAB, Pos.): m/z=478[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.88–0.95(2H, m), 1.04–1.23(3H, m),1.51–1.57(2H, m), 1.60–1.69(6H, m), 1.75(2H, d, J=12.4 Hz),2.69–2.73(2H, m), 2.88(2H, br), 3.24–3.28(2H, m), 3.71(2H, s), 4.12(4H,s), 7.53(2H, d, J=8.2 Hz), 7.61(4H, s), 7.78(2H, d, J=8.4 Hz), 8.55(2H,t, J=5.5 Hz), 8.59(2H, br).

Production Example 10 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(4-t-butyl-benzylamino)-butyl]-benzamide[Compound No. 10] Example 10-1 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(4-t-butyl-benzylamino)-butyl]-benzamide[Compound No. 10]

The compound (50.6 mg) obtained in Example 3-2 was dissolved inanhydrous methanol (2.0 ml) and added with 4-t-butyl-benzaldehyde(manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.0330 ml) and trimethylorthoformate (0.0430 ml), followed by stirring at room temperature for30 minutes. Then, the solution was added with sodium borohydride (14.8mg), followed by stirring at room temperature for 15 minutes. Aftercompletion of the reaction, the solvent was distilled off. The residuewas dissolved in chloroform and washed with a 1 mol/l sodium hydroxideaqueous solution and saturated saline solution, followed by drying withanhydrous magnesium sulfate. The solvent was distilled off and theresidue was then treated with hydrochloric acid. Subsequently, theresidue was purified through silica gel column chromatography(chloroform/methanol/water), thereby obtaining hydrochloride (42.0 mg)of the subject compound as a white solid.

MS(FAB, Pos.): m/z=528[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=1.28(9H, s), 1.53–1.56(2H, m), 1.67(2H, m),2.91(2H, br), 3.25(2H, d, J=6.3 Hz), 3.71(2H, s), 4.07(2H, t, J=5.5 Hz),4.11(4H, s), 7.45(4H, d, J=2.1 Hz), 7.52(8.2 Hz), 7.60(4H, s), 7.77(2H,d, J=8.2 Hz), 8.53(1H, t, J=5.6 Hz), 9.08(1H, br).

Production Example 11 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(2-trifluoromethyl)-benzylamino-butyl]-benzamide[Compound No. 11] Example 11-1 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(2-trifluoromethyl)-benzylamino-butyl]-benzamide[Compound No. 11]

The compound (50.6 mg) obtained in Example 3-2 was dissolved inanhydrous methanol (2.0 ml) and added with 2-trifluoromethylbenzaldehyde(manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.0260 ml) and trimethylorthoformate (0.0430 ml), followed by stirring at room temperature for30 minutes. Then, the solution was added with sodium borohydride (14.8mg), followed by stirring at room temperature for 15 minutes. Aftercompletion of the reaction, the solvent was distilled off. The residuewas dissolved in chloroform and washed with a 1 mol/l sodium hydroxideaqueous solution and saturated saline solution, followed by drying withanhydrous magnesium sulfate. The solvent was distilled off and theresidue was then treated with hydrochloric acid. Subsequently, theresidue was purified through silica gel column chromatography(chloroform/methanol/water), thereby obtaining hydrochloride (57.1 mg)of the subject compound as a white solid.

MS(FAB, Pos.): m/z=540[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=1.57–1.60 (2H, m), 1.69–1.70(2H, m),3.07(2H, t, J=7.6 Hz), 3.28(2H, t, J=6.8 Hz), 3.74(2H, s), 4.10(4H, s),4.30(2H, s), 7.45(2H, d, J=8.3 Hz), 7.57(4H, s), 7.67–7.85(6H, m).

Production Example 12 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(2-trifluoromethoxy)-benzylamino-butyl]-benzamide[Compound No. 12] Example 12-1 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(2-trifluoromethoxy)-benzylamino-butyl]-benzamide[Compound No. 12]

The compound (50.6 mg) obtained in Example 3-2 was dissolved inanhydrous methanol (2.0 ml) and added with2-trifluoromethoxybenzaldehyde (manufactured by Avocado Co., Ltd.)(0.0290 ml) and trimethyl orthoformate (0.0430 ml), followed by stirringat room temperature for 30 minutes. Then, the solution was added withsodium borohydride (14.8 mg), followed by stirring at room temperaturefor 15 minutes. After completion of the reaction, the solvent wasdistilled off. The residue was dissolved in chloroform and washed with a1 mol/l sodium hydroxide aqueous solution and saturated saline solution,followed by drying with anhydrous magnesium sulfate. The solvent wasdistilled off and the residue was then treated with hydrochloric acid.Subsequently, the residue was purified through silica gel columnchromatography (chloroform/methanol/water), thereby obtaininghydrochloride (39.7 mg) of the subject compound as a white solid.

MS(FAB, Pos.): m/z=556[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=1.55–1.57(2H, m), 1.68–1.70(2H, m), 2.99(2H,br), 3.26(2H, d, J=6.0 Hz), 3.71(2H, s), 4.10(4H, s), 4.20(2H, s),7.45–7.53(4H, m), 7.56–7.59(1H, m), 7.77–7.82(3H, m), 8.53(1H, t, J=5.5Hz), 9.24(2H, br).

Production Example 13 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(4-methylsulfanyl-benzylamino)-butyl]-benzamide[Compound No. 13] Example 13-1 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(4-methylsulfanyl-benzylamino)-butyl]-benzamide[Compound No. 13]

The compound (50.6 mg) obtained in Example 3-2 was dissolved inanhydrous methanol (2.0 ml) and added with 4-methylthiobenzaldehyde(manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.0270 ml) and trimethylorthoformate (0.0430 ml), followed by stirring at room temperature for30 minutes. Then, the solution was added with sodium borohydride (14.8mg), followed by stirring at room temperature for 15 minutes. Aftercompletion of the reaction, the solvent was distilled off. The residuewas dissolved in chloroform and washed with a 1 mol/l sodium hydroxideaqueous solution and saturated saline solution, followed by drying withanhydrous magnesium sulfate. The solvent was distilled off and theresidue was then treated with hydrochloric acid. Subsequently, theresidue was purified through silica gel column chromatography(chloroform/methanol/water), thereby obtaining hydrochloride (64.0 mg)of the subject compound as a white solid.

MS(FAB, Pos.): m/z=518[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=1.50–1.59(2H, m), 1.61–1.70(2H, m), 2.48(3H,s), 2.88(2H, br), 3.24(2H, d, J=5.8 Hz), 3.71(2H, s), 4.07(2H, m),4.11(4H, s), 7.29(2H, d, J=8.4 Hz), 7.46(2H, d, J=8.4 Hz), 7.52(2h, d,J=8.2 Hz), 7.60(4H, s), 7.77(2H, d, J=8.4 Hz), 8.52(1H, t, J=5.5 Hz),9.09(2H, br).

Production Example 14 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-{4-[(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-benzamide[Compound No. 14] Example 14-1 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-{4-[(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-benzamide[Compound No. 14]

The compound (50.6 mg) obtained in Example 3-2 was dissolved inanhydrous methanol (2.0 ml) and added with3-methylpyridine-2-carboxaldehyde (24.2 mg) and trimethyl orthoformate(0.0430 ml), followed by stirring at room temperature for 30 minutes.Then, the solution was added with sodium borohydride (14.8 mg), followedby stirring at room temperature for 15 minutes. After completion of thereaction, the solvent was distilled off. The residue was dissolved inchloroform and washed with a 1 mol/l sodium hydroxide aqueous solutionand saturated saline solution, followed by drying with anhydrousmagnesium sulfate. The solvent was distilled off and the residue wasthen treated with hydrochloric acid. Subsequently, the residue waspurified through silica gel column chromatography(chloroform/methanol/water), thereby obtaining hydrochloride (59.3 mg)of the subject compound as a white solid.

MS(FAB, Pos.): m/z=487[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=1.56–1.61(2H, m), 1.73–1.75(2H, m), 2.29(3H,s), 3.03–3.06(2H, m), 3.27(2H, dd, J=6.3, 12.4 Hz), 3.71(2H, s),4.12(4H, s), 4.33(2H, t, J=5.8 Hz), 7.34–7.36(1H, m), 7.54(2H, d, J=8.2Hz), 7.61(4H, s), 7.70(1H, d, J=7.8 Hz), 7.78(2H, d, J=8.2 Hz), 8.45(1H,d, J=3.7 Hz), 8.55(1H, t, J=5.5 Hz), 9.13(2H, br), 12.68(3H, br).

Production Example 15 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminophenyl)-benzamide[Compound No. 15] Example 15-1 Synthesis ofN,N-dipropyl-N′-Boc-1,4-phenylenediamine

N-Boc-1,4-phenylenediamine (manufactured by Furka Co., Ltd.) (589 mg)was dissolved in anhydrous methanol (2.0 ml) and then added with sodiumcyanoborohydride (533 mg), trimethyl orthoformate (774 μl), andpropionaldehyde (510 μl), followed by stirring overnight under anitrogen atmosphere at room temperature. After completion of thereaction, the solvent was distilled off. Then, the residue was thendissolved in chloroform and added with a saturated aqueous sodiumbicarbonate solution, followed by stirring. This solution was subjectedto extraction with chloroform and the extract was then washed with asaturated aqueous sodium bicarbonate solution and saturated salinesolution. The organic layer was dried with anhydrous sodium sulfate. Thesolvent was distilled off and the residue was then purified throughsilica gel column chromatography (chloroform), thereby obtaining thesubject compound (863 mg) as an auburn liquid.

MS(FAB, Pos.): m/z=292[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=0.90(6H, t, J=7.6 Hz), 1.50(9H, s), 1.57(4H,sext., J=7.6 Hz), 3.18(4H, t, J=7.6 Hz), 6.22(1H, brs), 6.58(2H, d,J=9.0 Hz), 7.15(2H, br).

Production Example 15-2 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminophenyl)-benzamide[Compound No. 15]

The compound (300 mg) obtained in Example 2-2 was dissolved in DMF (10ml) and added with DCC (298 mg), HOBt (195 mg), and the compound (185mg) obtained in Example 15-1, followed by stirring overnight at roomtemperature. After completion of the reaction, the solvent was distilledoff and the residue was then dissolved in chloroform, followed byseparating the solution into layers by the addition of 1 mol/lhydrochloric acid. The aqueous layer was made basic by the addition of a1 mol/l sodium hydroxide aqueous solution. Then, the solution wassubjected to extraction with chloroform. The extract was washed withsaturated saline solution and the organic layer was then dried withanhydrous sodium sulfate. The solvent was distilled off. Subsequently,the residue was treated with hydrochloric acid and then purified throughsilica gel column chromatography (chloroform/methanol/water), therebyobtaining hydrochloride (96.4 mg) of the subject compound as a whitesolid.

MS(FAB, Pos.): m/z=486[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.83(6H, t, J=6.9 Hz), 1.12–1.30(2H, m),1.66(2H, brs), 3.44(4H, m), 3.76(2H, s), 4.16(4H, s), 7.62(6H, brs),7.79(2H, brs), 7.94(2H, d, J=7.6 Hz), 7.99(2H, brs), 10.6(1H, brs),12.7(1H, brs), 14.8(1H, brs).

Production Example 16 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-{4-[bis(3-methyl-butyl)-amino]butyl}-benzamide[Compound No. 16] Example 16-1 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-{4-[bis(3-methyl-butyl)-amino]butyl}-benzamide[Compound No. 16]

The compound (30.0 mg) obtained in Example 3-2 was dissolved in methanol(0.6 ml). Then, the solution was added with trimethyl orthoformate (30.0μl), acetic acid (30.0 μl), isovaleraldehyde (manufactured by TokyoKasei Kogyo Co., Ltd.) (25.3 μl), and sodium cyanoborohydride (14.9 mg),followed by stirring at room temperature for 3 hours.

After completion of the reaction, the solvent was distilled off underreduced pressure and the residue was then dissolved in chloroform. Afterthe residue had been washed with a 1 mol/l sodium hydroxide aqueoussolution, the objective substance was transferred to the aqueous layerby the addition of 1 mol/l hydrochloric acid, followed by washing withchloroform. The 1 mol/l sodium hydroxide aqueous solution was addedagain to alkalinize the solution, followed by extraction withchloroform. Then, the extract was washed with saturated saline solutionand then dried with anhydrous sodium sulfate. After filtration, thesolvent was distilled off under reduced pressure and the residue wasdried under vacuum. Subsequently, the residue was treated withhydrochloric acid, thereby obtaining hydrochloride (21.8 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=522[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.87(12H, d, J=6.1 Hz), 1.46–1.60(8H, m),1.67(2H, br), 2.98–3.04(6H, m), 3.28(2H, d, J=5.8 Hz), 3.71(2H, s),4.13(4H, s), 7.54(2H, d, J=8.1 Hz), 7.61(4H, s), 7.79(2H, d, J=8.2 Hz),8.57(1H, t, J=5.8 Hz), 10.23(1H, brs).

Production Example 17 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dimethylamino-butyl)-benzamide[Compound No. 17] Example 17-1 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dimethylamino-butyl)-benzamide[Compound No. 17]

The compound (27.7 mg) obtained in Example 3-2 was dissolved inanhydrous methanol (1.1 ml). Then, the solution was added with a 36%formaldehyde aqueous solution (manufactured by Kanto Kagaku) (0.0160 ml)and sodium cyanoborohydride (13.2 mg) and adjusted to pH 5 with aceticacid, followed by stirring at room temperature for 22 hours. Aftercompletion of the reaction, the solvent was distilled off and theresidue was then dissolved in chloroform, followed by washing with a 1mol/l sodium hydroxide aqueous solution and saturated saline solutionand drying with anhydrous magnesium sulfate. The solvent was distilledoff and the residue was then treated with hydrochloric acid.Subsequently, the residue was purified through a solid-phase extractioncolumn (Sep-Pack®, tC18, manufactured by Waters Corporation), therebyobtaining hydrochloride (16.4 mg) of the subject compound as a whitesolid.

MS(FAB, Pos.): m/z=410[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=1.51–1.54(2H, m), 1.65(2H, m), 2.73(6H, d,J=4.9 Hz), 3.03–3.04(2H, m), 3.26(2H, d, J=5.6 Hz), 3.72(2H, s),4.08(4H, s), 7.51(2H, d, J=8.5 Hz), 7.59(4H, s), 7.77(2H, d, J=8.3 Hz),8.52(1H, t, J=5.5 Hz).

Production Example 18 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-cycloheptylaminobutyl)-benzamide[Compound No. 18] Example 18-1 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-cycloheptylaminobutyl)-benzamide[Compound No. 18]

The compound (30.0 mg) obtained in Example 3-2 was dissolved in methanol(0.6 ml). This solution was added with trimethyl orthoformate (30.0 μl),acetic acid (30.0 μl), cycloheptanone (manufactured by Merck, Inc.)(18.7 μl), and sodium cyanoborohydride (14.9 mg), followed by stirringfor 3 hours at room temperature. After completion of the reaction, thesolvent was distilled off under reduced pressure. Then, the residue wasdissolved in chloroform, washed with a 1 mol/l sodium hydroxide aqueoussolution, and added with 1 mol/l hydrochloric acid to transfer theobjective substance to the aqueous layer, followed by washing withchloroform. The 1 mol/l sodium hydroxide aqueous solution was addedagain to alkalinize the solution. The solution was subjected toextraction with chloroform and the extract was then washed withsaturated saline solution and dried with anhydrous sodium sulfate. Afterfiltration, the solvent was distilled off under reduced pressure. Then,the residue was dried under vacuum and treated with hydrochloric acid,thereby obtaining hydrochloride (32.2 mg) of the subject compound as awhite solid.

MS(FAB, Pos.): m/z=478[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=1.29–1.66(14H, m), 2.00–2.03(2H, m),2.88(2H, br), 3.06–3.12(1H, m), 3.26(2H, d, J=6.1 Hz), 3.71(2H, s),4.13(4H, s), 7.53(2H, d, J=8.2 Hz), 7.61(4H, s), 7.78(2H, d, J=8.4 Hz),8.57(1H, t, J=6.1 Hz), 8.69(1H, brs).

Production Example 19 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide[Compound No. 19] Example 19-1 Synthesis of (4-nitrobenzyl)dipropylamine

Commercially available 4-nitrobenzylamine hydrochloride (manufactured byTokyo Kasei Kogyo., Ltd.) (1.82 g) was suspended in chloroform (15 ml).Then, a 1 mol/l sodium hydroxide aqueous solution (15 ml) was added tothe suspension and the aqueous layer was then extracted with chloroform.The extract was dried with anhydrous magnesium sulfate and the solventwas then distilled off, followed by dissolving the residue in anhydrousmethanol (20 ml). Subsequently, the solution was added withpropionaldehyde (1.66 ml) and sodium cyanoborohydride (1.81 g) and thenadjusted to pH 5 with acetic acid, followed by stirring at roomtemperature for 21 hours. After completion of the reaction, the solventwas distilled off. The residue was added with 1 mol/l sodium hydroxideand then subjected to chloroform extraction. The extract was dried withanhydrous magnesium sulfate and the solvent was then distilled off. Theresidue was purified through silica gel column chromatography(hexane/ethyl acetate), thereby obtaining the subject compound (1.67 g)as a yellow oily substance.

¹H-NMR(500 MHz, CDCl₃): δ=0.87(6H, t, J=7.3 Hz), 1.47(4H, sext., J=7.3Hz), 2.38(4H, t, J=7.1 Hz), 3.63(2H, s), 7.52(2H, d, J=9.0 Hz), 8.16(2H,d, J=8.8 Hz).

Example 19-2 Synthesis of 4-dipropylaminomethyl phenylamine

The compound (492 mg) obtained in Example 19-1 was dissolved in methanol(5.0 ml) and THF (2.5 ml). Then, the solution was added with activatedcarbon (49.0 mg) and iron trichloride hexahydrate (manufactured by KantoKagaku) (4.90 mg), followed by refluxing under heating for 30 minutes.After the solution was cooled to room temperature, hydrazine monohydrate(0.35 ml) was added to the solution and then the whole was refluxed for3 hours under heat. After completion of the reaction, the reactionproduct was filtrated through Celite and the solvent was then distilledoff. After the addition of water, chloroform extraction was performed.The extract was dried with anhydrous magnesium sulfate. The solvent wasdistilled off, thereby obtaining the subject compound (437 mg) as ayellow oily substance.

MS(FAB, Pos.): m/z=207[M+H]⁺

Example 19-3 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide[Compound No. 19]

The compound (57.2 mg) obtained in Example 19-2, the compound (106 mg)obtained in Example 2-2, and HOBt (162 mg) were dissolved in anhydrousDMF (2.5 ml) and then added with PS-carbodiimide (manufactured byArgonaut Technologies, Inc.) (419 mg), followed by stirring at roomtemperature for 12 hours. After completion of the reaction, the solutionwas filtrated and the solvent was then distilled off. The residue wasdissolved in chloroform and then washed with 1 mol/l sodium hydroxideand saturated saline solution, followed by drying with anhydrousmagnesium sulfate. The solvent was distilled off and the residue wasthen treated with hydrochloric acid. Subsequently, the residue waspurified through silica gel column chromatography(chloroform/methanol/water), thereby obtaining hydrochloride (18.3 mg)of the subject compound as a yellow solid.

MS(FAB, Pos.): m/z=500[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.87(6H, t, J=7.3 Hz), 1.67–1.77(4H, m),2.88–2.93(4H, m), 3.76(2H, s), 4.14(4H, s), 4.26(2H, d, J=5.2 Hz),7.56(2H, d, J=8.5 Hz), 7.62(4H, s), 7.88(2H, d, J=8.7 Hz), 7.91(2H, d,J=8.2 Hz), 10.18(1H, br), 10.39(1H, s).

Production Example 20 Synthesis ofN-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 20] Example 20-1 Synthesis ofN-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 20]

The compound (39.8 mg) obtained in Example 1-3 and pyridine-2-aldehyde(manufactured by Tokyo Kasei Kogyo Co., Ltd.) (16.1 mg) were dissolvedin anhydrous methanol (2.0 ml). The solution was added with sodiumcyanoborohydride (18.9 mg) and then adjusted to pH 5 with acetic acid,followed by stirring at room temperature for 39.5 hours. Aftercompletion of the reaction, the solvent was distilled off. The residuewas dissolved in chloroform and then washed with a 1 mol/l sodiumhydroxide and saturated saline solution, followed by drying withanhydrous magnesium sulfate. Subsequently, the residue was distilled offand the residue was then treated with hydrochloric acid. The residue waspurified through silica gel column chromatography(chloroform/methanol/water), thereby obtaining hydrochloride (7.00 mg)of the subject compound as a yellow solid.

MS(FAB, Pos.): m/z=478[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.89(6H, t, J=7.3 Hz), 1.53–1.56(2H, m),1.61–1.69(4H, m), 2.94–3.01(4H, m), 3.04(2H, br), 3.28(2H, d, J=6.0 Hz),3.76(2H, s), 3.95(2H, br), 4.10(2H, s), 7.50(2H, d, J=8.4 Hz), 7.60(2H,s), 7.79(2H, d, J=8.2 Hz), 8.54(1H, t, J=5.5 Hz), 8.63–8.67(2H, m),9.83(1H, br).

Production Example 21 Synthesis ofN-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(thiazol-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 21] Example 21-1 Synthesis ofN-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(thiazol-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 21]

The compound (39.8 mg) obtained in Example 1-3 and 2-formylthiazole(manufactured by Tokyo Kasei Kogyo Co., Ltd.) (16.9 mg) were dissolvedin anhydrous methanol (2.0 ml) and then added with sodiumcyanoborohydride (18.9 mg). The solution was adjusted to pH 5 withacetic acid and then stirred at room temperature for 39.5 hours. Aftercompletion of the reaction, the solvent was distilled off. The residuewas dissolved in chloroform and then washed with 1 mol/l sodiumhydroxide and saturated saline solution, followed by drying withanhydrous magnesium sulfate. The solvent was distilled off and theresidue was then treated with hydrochloric acid. The residue waspurified through silica gel column chromatography(chloroform/methanol/water) thereby obtaining hydrochloride (9.20 mg) ofthe subject compound as a white solid.

MS(FAB, Pos.): m/z=483[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.89(6H, t, J=7.3 Hz), 1.61–1.75(8H, m),3.00–3.05(6H, m), 3.30–3.37(2H, m), 3.81(2H, s), 4.03(2H, s), 4.12(2H,s), 7.50–7.52(3H, m), 7.59(2H, s), 7.71(1H, d, J=3.4 Hz), 7.77(1H, d,J=3.4 Hz), 7.83(2H, d, J=8.4 Hz), 8.56(1H, t, J=5.6 Hz), 9.74(1H, br).

Production Example 22 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(3-dipropylaminopropyl)-benzamide[Compound No. 22] Example 22-1 Synthesis of N-Boc-1,3-propanediamine

1,3-propanediamine (manufactured by Kanto Kagaku) (2.57 g) was dissolvedin anhydrous dichloromethane (75 ml) and then added with triethylamine(4.80 ml) and di-t-butoxydicarbonate (3.78 g), followed by stirringovernight under a nitrogen atmosphere at room temperature. Aftercompletion of the reaction, the solution was added with water and thenstirred, followed by extraction with dichloromethane. The organic layerwas washed with saturated saline solution and then dried with anhydroussodium sulfate. The solvent was distilled off, thereby obtaining thesubject compound (3.15 g) as a colorless liquid.

MS(FAB, Pos.): m/z=175[M+H]⁺

Example 22-2 Synthesis of N,N-dipropyl-N′-Boc-1,3-propanediamine

The compound (1.50 g) obtained in Example 22-1 was dissolved inanhydrous methanol (20 ml) and added with sodium cyanoborohydride (1.62g), trimethyl orthoformate (2.35 ml), and propionaldehyde (1.55 ml),followed by stirring under a nitrogen atmosphere at room temperature for3 days. After completion of the reaction, the solvent was distilled off.Then, the residue was dissolved in chloroform and added with a saturatedaqueous sodium bicarbonate solution, followed by stirring. The solutionwas subjected to extraction with chloroform and then washed with asaturated aqueous sodium bicarbonate solution and saturated salinesolution. Subsequently, the organic layer was dried with anhydroussodium sulfate. The solvent was distilled off, thereby the subjectcompound (2.67 g) as a colorless liquid.

MS(FAB, Pos.): m/z=259[M+H]⁺

Example 22-3 Synthesis of N,N-dipropyl-1,3-propanediamine

The compound (2.67 g) obtained in Example 22-2 was dissolved inanhydrous methanol (2.0 ml) and then added with a 4 mol/l hydrogenchloride/dioxane solution (20.0 ml), followed by stirring at roomtemperature for 1.5 hours. After completion of the reaction, the solventwas distilled off. Then, the residue was added with a 1 mol/l sodiumhydroxide aqueous solution and extracted with dichloromethane. Theextract was washed with distilled water and saturated saline solution,and then the organic layer was dried with anhydrous sodium sulfate.Subsequently, the solvent was distilled off, thereby obtaining thesubject compound (726 mg) as a pale-yellow liquid.

MS(FAB, Pos.): m/z=159[M+H]⁺

Example 22-4 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(3-dipropylaminopropyl)-benzamide[Compound No. 22]

The compound (190 mg) obtained in Example 2-2 was dissolved in DMF (3.0ml) and added with DCC (189 mg), HOBt (124 mg), and the compound (96.9mg) obtained in Example 22-3, followed by stirring overnight at roomtemperature. After completion of the reaction, the solvent was distilledoff and the residue was then dissolved in chloroform, followed byseparating the solution into layers by the addition of 1 mol/lhydrochloric acid. The aqueous layer was made basic with a 1 mol/lsodium hydroxide aqueous solution. Then, the solution was subjected toextraction with chloroform. The extract was washed with saturated salinesolution and the organic layer was then dried with anhydrous sodiumsulfate. The solvent was distilled off. Subsequently, the residue wastreated with hydrochloric acid and then purified through silica gelcolumn chromatography (chloroform/methanol/water), thereby obtaininghydrochloride (84.8 mg) of the subject compound as a white solid.

MS(FAB, Pos.): m/z=452[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.89(6H, t, J=7.3 Hz), 1.65(4H, sext., J=7.3Hz), 1.86–1.94(2H, m), 2.95–2.99(4H, m), 3.04–3.09(2H, m), 3.32(2H, m),3.72(2H, s), 4.13(4H, s), 7.54(2H, d, J=8.4 Hz), 7.60(4H, s), 7.78(2H,d, J=8.4 Hz), 8.68(1H, t, J=5.8 Hz), 10.2(1H, brs).

Production Example 23 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(3-dipropylamino-2,2-dimethylpropyl)-benzamide[Compound No. 23] Example 23-1 Synthesis ofN-Boc-2,2-dimethyl-1,3-propanediamine

2,2-dimethyl-1,3-propanediamine (manufactured by Aldrich Corporation)(2.00 g) was dissolved in anhydrous dichloromethane (100 ml) and thenadded with triethylamine (2.70 ml) and di-t-butoxydicarbonate (2.14 g),followed by stirring overnight under a nitrogen atmosphere at roomtemperature. After completion of the reaction, the solution was addedwith water and stirred, followed by extraction with dichloromethane. Theorganic layer was washed with saturated saline solution and then driedwith anhydrous sodium sulfate. The solvent was distilled off, therebyobtaining the subject compound (1.76 g) as a white solid.

MS(FAB, Pos.): m/z=203[M+H]⁺

Example 23-2 Synthesis of(N,N-dipropyl-N′-Boc)-2,2-dimethyl-1,3-propanediamine

The compound (501 mg) obtained in Example 23-1 was dissolved inanhydrous methanol (5.0 ml) and then added with sodium cyanoborohydride(467 mg), trimethyl orthoformate (677 μl), and propionaldehyde (447 μl),followed by stirring at room temperature under a nitrogen atmosphere for3 days. After completion of the reaction, the solvent was distilled off.Then, the residue was dissolved in chloroform and added with a saturatedaqueous sodium bicarbonate solution, followed by stirring. The solutionwas extracted with chloroform and the extract was washed with asaturated aqueous sodium bicarbonate solution and saturated salinesolution. The organic layer was dried with anhydrous sodium sulfate. Thesolvent was distilled off, thereby obtaining the subject compound (740mg) as a pale-yellow liquid.

MS(FAB, Pos.): m/z=287[M+H]⁺

Example 23-3 Synthesis of N,N-dipropyl-2,2-dimethyl-1,3-propanediamine

The compound (740 mg) obtained in Example 23-2 was dissolved inanhydrous methanol (3.0 ml) and then added with a 4 mol/l hydrogenchloride/dioxane solution (15.0 ml), followed by stirring at roomtemperature for 1 hour. After completion of the reaction, the solventwas distilled off and the residue was then added with a 1 mol/l sodiumhydroxide aqueous solution, followed by extraction with dichloromethane.After the extract had been washed with distilled water and saturatedsaline solution, the organic layer was dried with anhydrous sodiumsulfate. The solvent was then distilled off, thereby obtaining thesubject compound (351 mg) as a colorless liquid.

MS(FAB, Pos.): m/z=187[M+H]⁺

Example 23-4 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(3-dipropylamino-2,2-dimethylpropyl)-benzamide[Compound No. 23]

The compound (100 mg) obtained in Example 2-2 was dissolved in DMF (2.0ml) and then added with DCC (55.4 mg), HOBt (36.3 mg), and the compound(50.0 mg) obtained in Example 23-3, followed by stirring overnight atroom temperature. After completion of the reaction, the solvent wasdistilled off and the residue was then dissolved in chloroform. Then,the solution was added with 1 mol/l hydrochloric acid to separate thesolution into layers. After the aqueous layer was added with a 1 mol/lsodium hydroxide aqueous solution to make the solution basic, thesolution was subjected to extraction with chloroform and the extract wasthen washed with saturated saline solution. Subsequently, the organiclayer was dried with anhydrous sodium sulfate. The solvent was distilledoff and the residue was then treated with hydrochloric acid. After that,the residue was subjected to purification through silica gel columnchromatography (chloroform/methanol/water), thereby obtaininghydrochloride (17.5 mg) of the subject compound as a white solid.

MS(FAB, Pos.): m/z=480[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.89(6H, t, J=7.3 Hz), 1.09(6H, s),1.61–1.78(4H, m), 3.02–3.03(6H, m), 3.26–3.27(2H, m), 3.72(2H, s),4.12(4H, s), 7.58(2H, d, J=8.2 Hz), 7.61(4H, s), 7.82(2H, d, J=8.2 Hz),8.61–8.63(1H, m), 9.18(1H, brs).

Production Example 24 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminobutyl)-benzenesulfonamide[Compound No. 24] Example 24-1 Synthesis of 2-benzylisoindole-1,3-dione

Benzylamine (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (1.00 g) wasdissolved in purified water (20 ml) and then added withN-carbethoxyphthalimide (manufactured by Tokyo Kasei Kogyo Co., Ltd.)(3.06 g) and sodium carbonate (2.47 g), followed by stirring at roomtemperature for 3 hours. After completion of the reaction, the solutionwas filtered and the residue was washed with purified water and thendried under vacuum at 60° C., thereby obtaining the subject compound(1.82 g) as a white solid.

MS(FAB, Pos.): m/z=238[M+H]⁺

Example 24-2 Synthesis of4-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)benzenesulfonylchloride

The compound (330 mg) obtained in Example 24-1 was dissolved inchloroform and then added with chlorosulfuric acid (manufactured byKishida Chemical Co., Ltd.) (0.177 ml) under ice-cooling. The solutionwas stirred at room temperature for 2 days, and then concentrated anddried. The resultant was gradually added with phosphorus pentachloride(300 mg) and then heated to 80° C., followed by stirring for 4 hours.

After completion of the reaction, the reacted solution was stood to cooland then dropped into ice cold water. The product was extracted withchloroform and then washed with a 5% aqueous sodium bicarbonate solutionand saturated saline solution. Subsequently, the product was dried withanhydrous sodium sulfate and then concentrated, thereby obtaining thesubject compound (440 mg) as a yellowish white solid.

MS(FAB, Pos.): m/z=336[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=4.95(2H, s), 7.66–7.68(2H, m), 7.74–7.77(2H,m), 7.87–7.90(2H, m), 7.99–8.01(2H, m).

Example 24-3 Synthesis of4-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-N-(4-dipropylaminobutyl)benzenesulfonamide

The compound (150 mg) obtained in Example 24-2 was dissolved inchloroform (10 ml) and then added with the compound (131 mg) obtained inExample 1-2 and triethylamine (0.224 ml), followed by stirring at roomtemperature for 15 minutes. The solution was added with water andsubjected to extraction. The organic layer was washed with saturatedsaline solution and then dried and concentrated with anhydrous sodiumsulfate, thereby obtaining the subject compound (160 mg) as a colorlessviscous liquid.

MS(FAB, Pos.): m/z=472[M+H]⁺

Example 24-4 Synthesis of4-aminomethyl-N-(4-dipropylaminobutyl)benzenesulfonamide

The compound (160 mg) obtained in Example 24-3 was added with 2.0 ml ofa 40% methylamine/methanol solution (manufactured by Tokyo Kasei KogyoCo., Ltd.), followed by stirring at room temperature for 40 hours. Aftercompletion of the reaction, the solvent was distilled off and theresidue was subjected to extraction by the addition of a 1 mol/l sodiumhydroxide aqueous solution and chloroform. The organic layer was driedwith anhydrous sodium sulfate and the solvent was distilled off, therebyobtaining the subject compound (114 mg) as a colorless viscous liquid.

MS(FAB, Pos.): m/z=342[M+H]⁺

Example 24-5 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminobutyl)-benzenesulfonamide[Compound No. 24]

The compound (114 mg) obtained in Example 24-4 was dissolved inanhydrous methanol (7.0 ml), and then the solution was added with2-imidazole carboxaldehyde (73.0 mg), sodium cyanoborohydride (42.0 mg),and acetic acid (0.1 ml) in that order, followed by stirring at roomtemperature for 2 days. The methanol was distilled off and a 1 mol/lsodium hydroxide aqueous solution (1.8 ml) was then added to theresidue. The solution was extracted with chloroform and the extract wasthen dried with anhydrous sodium sulfate, followed by distilling thesolvent off. Subsequently, the residue was purified through silica gelcolumn chromatography (chloroform/methanol/water) and then treated withhydrochloric acid, thereby obtaining hydrochloride (160 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=502[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.89(6H, t, J=7.4 Hz), 1.40–1.44(2H, m),1.60–1.70(6H, m), 2.67–2.72(2H, m), 2.93–3.01(6H, m), 3.76–3.80(2H, m),4.14–4.16(4H, m), 7.48–7.84(8H, m), 9.94(1H, brs).

Production Example 25 Synthesis ofN-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N′,N′-dipropylbutane-1,4-diamine[Compound No. 25] Example 25-1 Synthesis of4-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)benzaldehyde

Methyl 4-(aminomethyl)-benzoate hydrochloride (manufactured by AldrichCorporation) (773 mg) was dissolved in THF (50 ml) and then graduallyadded with lithium aluminum hydride (300 mg) under ice-cooling. Thesolution was stirred at room temperature for 3 hours and then cooledwith ice, followed by gradual addition of a concentrated sodiumhydroxide aqueous solution until foam was not observed. Celitefiltration was carried out on the solution using chloroform as a solventand then the filtrate was concentrated and dried. The dried product wasdissolved in purified water (10 ml) and THF (10 ml). After having beencooled with ice, the solution was added with N-carbethoxyphthalimide(1.26 g) and sodium carbonate (900 mg). After the mixture had beenstirred at room temperature for 4 hours, THF was distilled off andchloroform was then added to the residue to carry out extraction. Theorganic layer was dried with anhydrous sodium sulfate and the solventwas then distilled off. Subsequently, the residue was further driedunder vacuum. Next, this compound was dissolved in chloroform (20 ml)and then added with manganese dioxide (5.0 g), followed by stirring atroom temperature for 3 hours. After the solution had been subjected toCelite filtration, the filtrate was concentrated and then purifiedthrough silica gel column chromatography (chloroform/methanol), therebyobtaining the subject compound (259 mg) as a white solid.

MS(FAB, Pos.): m/z=266[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=4.92(2H, s), 7.58(2H, d, J=8.3 Hz),7.72–7.76(2H, m), 7.83–7.89(4H, m) 9.98(1H, s).

Example 25-2 Synthesis of 2-{4-[(4-dipropylaminobutylamino)-methyl]benzyl}isoindole-1,3-dione

The compound (103 mg) obtained in Example 25-1 was dissolved inanhydrous methanol (10 ml) and then added with the hydrochloride (114mg) of the compound obtained in Example 1-2. Then, the solution wasadded with triethylamine (0.108 ml) and anhydrous magnesium sulfate (3g), followed by stirring at room temperature for 1 hour. Anhydrousmagnesium sulfate was removed from the solution by Celite filtration.Then, methanol was distilled off and the residue was dried using avacuum pump. The residue was dissolved in anhydrous methanol (10 ml) andsodium borohydride (22.0 mg) was then gradually added under ice-cooling.The solution was warmed to room temperature and then stirred for 1 hour.After completion of the reaction, methanol was distilled off and theresidue was then added with water and chloroform to extract the organiclayer. After the organic layer had been dried with anhydrous sodiumsulfate, the solvent was distilled off and the residue was then purifiedthrough silica gel column chromatography (chloroform/methanol/water),thereby obtaining the subject compound (60.3 mg) as a pale-yellowviscous liquid.

MS(FAB, Pos.): m/z=420[M+H]⁺

Example 25-3 Synthesis of[4-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)benzyl]-(4-dipropylaminobutyl)carbamicacid t-butyl ester

The compound (60.3 mg) obtained in Example 25-2 was dissolved inchloroform and then added with di-t-butoxydicarbonate (47.0 mg). Afterhaving been stirred at room temperature for 30 minutes, the solution wassubjected to concentration and then purification through silica gelcolumn chromatography (chloroform/methanol), thereby obtaining thesubject compound (70.0 mg) as a colorless viscous liquid.

MS(FAB, Pos.): m/z=522[M+H]⁺

Example 25-4 Synthesis of(4-aminomethylbenzyl)-(4-dipropylaminobutyl)carbamic acid t-butyl ester

The compound (70.0 mg) obtained in Example 25-3 was added with a 40%methylamine/methanol solution (3.0 ml) and then stirred at roomtemperature for 14 hours. After completion of the reaction, the solventwas distilled off. Then, the residue was then added with a 1 mol/lsodium hydroxide aqueous solution and chloroform to extract the aqueouslayer therefrom with chloroform. The extract was dried with anhydroussodium sulfate, and the solvent was distilled off, thereby obtaining thesubject compound (65.5 mg) as a colorless viscous liquid.

Example 25-5 Synthesis ofN-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N′,N′-dipropylbutane-1,4-diamine[Compound No. 25]

The compound (45.5 mg) obtained in Example 25-4 was dissolved inanhydrous methanol (3.0 ml), and then the solution was added with2-imidazole carboxaldehyde (25.0 mg), sodium cyanoborohydride (15.0 mg),and acetic acid (0.1 ml) in that order, followed by stirring at roomtemperature for 15 hours. The methanol was distilled off and a 1 mol/lsodium hydroxide aqueous solution (1.0 ml) was then added to theresidue. The solution was extracted with chloroform and the extract wasthen dried with anhydrous sodium sulfate, followed by distilling thesolvent off. Subsequently, the residue was purified through silica gelcolumn chromatography (chloroform/methanol/water) and then treated withhydrochloric acid, thereby obtaining hydrochloride (28.0 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=452[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.90(6H, t, J=7.3 Hz), 1.62–1.78(8H, m),2.83(2H, brs), 2.93–3.04(8H, m), 3.67(2H, s), 4.05–4.10(2H, m), 4.11(4H,s), 7.46–7.50(4H, m), 7.60–7.64(4H, m), 9.40(2H, brs), 10.24(1H, brs),14.68(1H, brs).

Production Example 26 Synthesis ofN-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 26] Example 26-1 Synthesis ofN-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 26]

The compound (53.8 mg) obtained in Example 1-4 was dissolved in methanol(0.8 ml) and then added with trimethyl orthoformate (50 μl), acetic acid(50 μl), and 1-methyl-2-imidazolecarboxylaldehyde (manufactured byAldrich Corporation) (28.5 mg). After the solution had been stirred atroom temperature for 10 minutes, sodium cyanoborohydride (24.4 mg) wasadded and then the whole was stirred overnight at room temperature. Thesolvent was distilled off under reduced pressure and the residue wasthen dissolved in chloroform, followed by washing with 1 mol/l sodiumhydroxide and saturated saline solution and drying with anhydrous sodiumsulfate. After filtration, the solvent was distilled off under reducedpressure. The residue was purified through silica gel columnchromatography (chloroform/methanol) and then treated with hydrochloricacid, thereby obtaining hydrochloride (10.0 mg) of the subject compoundas a pale-yellow solid.

MS(FAB, Pos.) m/z=480[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.89(6H, t, J=7.3 Hz), 1.50–1.56(2H, m),1.62–1.74(6H, m), 2.94(4H, dt, J=4.6, 2.6 Hz), 3.02–3.06(2H, m),3.27(2H, q, J=6.4 Hz), 3.71(3H, s), 3.75(2H, s), 4.09(2H, s), 4.17(2H,s), 7.50(2H, d, J=8.2 Hz), 7.54(2H, d, J=8.2 Hz), 7.64(2H, s), 7.79(1H,d, J=8.4 Hz), 8.59(1H, t, J=5.5 Hz), 10.32(1H, brs).

Production Example 27 Synthesis ofN-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(1H-pyrazol-3-ylmethyl)-amino]-methyl}-benzamide[Compound No. 27] Example 27-1 Synthesis ofN-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(1H-pyrazol-3-ylmethyl)-amino]-methyl}-benzamide[Compound No. 27]

The compound (53.8 mg) obtained in Example 1-4 was dissolved in methanol(0.8 ml). Then, the solution was added with trimethyl orthoformate (50μl), acetic acid (50 μl), and pyrazol-3-carboxaldehyde (manufactured byMerck, Inc.) (24.9 mg) and stirred at room temperature for 10 minutes.Subsequently, sodium cyanoborohydride (24.4 mg) was added, followed bystirring overnight at room temperature. The solvent was distilled offunder reduced pressure and then the residue was dissolved in chloroform,followed by washing with 1 mol/l sodium hydroxide and saturated salinesolution and drying with anhydrous sodium sulfate. After filtration, thesolvent was distilled off under reduced pressure. Then, the residue wasthen purified through silica gel column chromatography(chloroform/methanol) and treated with hydrochloric acid, therebyobtaining hydrochloride (26.1 mg) of the subject compound as a whitesolid.

MS(FAB, Pos.): m/z=466[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.88(6H, t, J=7.3 Hz), 1.53–1.69(8H, m),2.95(4H, brs), 3.05(2H, brs), 3.25–3.40(2H, m), 3.55(2H, s), 3.58(2H,s), 3.62(2H, s), 6.27(1H, s), 7.04(2H, s), 7.50(2H, d, J=8.2 Hz),7.81(2H, d, J=8.2 Hz), 8.51(1H, t, J=5.5 Hz).

Production Example 28 Synthesis ofN-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-((2R)-pyrrolidin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 28] Example 28-1 Synthesis ofN-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-((2R)-pyrrolidin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 28]

The compound (53.8 mg) obtained in Example 1-4 was dissolved in methanol(0.8 ml). Then, the solution was added with trimethyl orthoformate (50μl), acetic acid (50 μl), N-Boc-D-prolinal (manufactured by AldrichCorporation) (25.7 mg) and stirred at room temperature for 10 minutes.Subsequently, sodium cyanoborohydride (24.4 mg) was added, followed bystirring overnight at room temperature. The solvent was distilled offunder reduced pressure and the residue was then dissolved in chloroform,followed by washing with 1 mol/l sodium hydroxide and saturated salinesolution and drying with anhydrous sodium sulfate. After filtration, thesolvent was distilled off under reduced pressure and the residue wasthen purified through silica gel column chromatography(chloroform/methanol). Then, the purified product was dissolved inmethanol (500 μl) and added with a 4 mol/l hydrogen chloride/dioxanesolution (500 μl), followed by stirring at room temperature for 2 hours.After completion of the reaction, the solvent was distilled off underreduced pressure and the residue was then purified through silica gelcolumn chromatography (chloroform/methanol), thereby obtaininghydrochloride (33.9 mg) of the subject compound as a white solid.

MS(FAB, Pos.) m/z=469[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.89(6H, t, J=7.3 Hz), 1.45–1.58(3H, m),1.63–1.73(6H, m), 1.83–1.94(2H, m), 2.00–2.05(1H, m), 2.77(1H, dd,J=3.8, 9.9 Hz), 2.90–2.98(5H, m), 3.03–3.07(2H, m), 3.09–3.23(1H, m),3.28(2H, m), 3.60–3.86(4H, m), 3.95(1H, d, J=15.6 Hz), 4.15(1H, d,J=15.6 Hz), 7.45(2H, d, J=8.2 Hz), 7.49(2H, s), 7.78(2H, d, J=8.2 Hz),8.58(1H, t, J=5.6 Hz), 8.94(1H, brs), 9.82(1H, brs), 10.21(1H, brs).

Production Example 29 Synthesis ofN-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-((2S)-pyrrolidin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 29] Example 29-1 Synthesis ofN-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-((2S)-pyrrolidin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 29]

The compound (53.8 mg) obtained in Example 1-4 was dissolved in methanol(0.8 ml). Then, the solution was added with trimethyl orthoformate (50μl), acetic acid (50 μl), N-Boc-L-prolinal (manufactured by AldrichCorporation) (25.7 mg) and stirred at room temperature for 10 minutes.Subsequently, sodium cyanoborohydride (24.4 mg) was added, followed bystirring overnight at room temperature. The solvent was distilled offunder reduced pressure and the residue was then dissolved in chloroform,followed by washing with 1 mol/l sodium hydroxide and saturated salinesolution and drying with anhydrous sodium sulfate. After filtration, thesolvent was distilled off under reduced pressure and the residue wasthen purified through silica gel column chromatography(chloroform/methanol). Then, the purified product was dissolved inmethanol (500 μl) and added with a 4 mol/l hydrogen chloride/dioxanesolution, followed by stirring at room temperature for 2 hours. Aftercompletion of the reaction, the solvent was distilled off under reducedpressure and the residue was then purified through silica gel columnchromatography (chloroform/methanol), thereby obtaining hydrochloride(20.5 mg) of the subject compound as a pale brown solid.

MS(FAB, Pos.) m/z=469[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.89(6H, t, J=7.3 Hz), 1.47–1.58(3H, m),1.63–1.73(6H, m), 1.83–1.91(2H, m), 2.02–2.05(1H, m), 2.78(1H, dd,J=3.8, 9.9 Hz), 2.91–2.98(5H, m), 3.03–3.07(2H, m), 3.09–3.23(1H, m),3.26–3.30(2H, m), 3.57–3.71(2H, m), 3.81(2H, d, J=14.0 Hz), 3.96(1H, d,J=15.6 Hz), 4.15(1H, d, J=15.6 Hz), 7.45(2H, d, J=8.2 Hz), 7.49(2H, s),7.78(2H, d, J=8.2 Hz), 8.59(1H, t, J=5.6 Hz), 8.97(1H, brs), 9.85(1H,brs), 10.25(1H, brs).

Production Example 30 Synthesis ofN-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(4-methyl-1H-imidazol-5-ylmethyl)-amino]-methyl}-benzamide[Compound No. 30] Example 30-1 Synthesis ofN-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(4-methyl-1H-imidazol-5-ylmethyl)-amino]-methyl}-benzamide[Compound No. 30]

The compound (53.8 mg) obtained in Example 1-4 was dissolved in methanol(0.8 ml). Then, the solution was added with trimethyl orthoformate (50μl), acetic acid (50 μl), and 4-methyl-5-imidazole carboxaldehyde(manufactured by Aldrich Corporation) (28.5 mg) and stirred at roomtemperature for 10 minutes. Subsequently, sodium cyanoborohydride (24.4mg) was added, followed by stirring overnight at room temperature. Thesolvent was distilled off under reduced pressure and then the residuewas dissolved in chloroform, followed by washing with 1 mol/l sodiumhydroxide and saturated saline solution and drying with anhydrous sodiumsulfate. After filtration, the solvent was distilled off under reducedpressure and the residue was then purified through silica gel columnchromatography (chloroform/methanol) and then treated with hydrochloricacid, thereby obtaining hydrochloride (33.5 mg) of the subject compoundas a white solid.

MS(FAB, Pos.) m/z=480[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.81(6H, t, J=7.3 Hz), 1.32–1.43(6H, m),1.51(2H, quint., J=7.1 Hz), 2.04(3H, br), 2.28(4H, t, J=7.1 Hz),2.35(2H, t, J=7.1 Hz), 3.24(2H, dd, J=6.8, 5.9 Hz), 3.31–3.47(2H, m),3.56(4H, br), 6.85(1H, br), 7.10(1H, br), 7.47(2H, d, J=7.8 Hz),7.51(1H, s), 7.78(2H, d, J=8.3 Hz), 8.40(1H, t, J=5.9 Hz).

Production Example 31 Synthesis of(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-(4-dipropylaminopiperidin-1-yl)-methanone[Compound No. 31] Example 31-1 Synthesis of4-N,N-dipropylaminopiperidine

In methanol (9.0 ml), 4-amino-1-benzylpiperidine (manufactured by AcrossCo., Ltd.) (571 mg) was dissolved. Then, the solution was added withtrimethyl orthoformate (570 μl) and propionaldehyde (645 μl) and stirredat room temperature for 14 hours. After completion of the reaction, thesolvent was distilled off under reduced pressure and the residue wasthen dissolved in chloroform. After having been washed with 1 mol/lsodium hydroxide, the solution was extracted with chloroform. Theresulting organic layer was washed with saturated saline solution,followed by drying with anhydrous sodium sulfate. After filtration, thesolvent was distilled off under reduced pressure and the residue wasthen purified through silica gel column chromatography(chloroform/methanol). The purified product was dissolved in ethanol (50ml) and then added with 10% palladium-carbon (50.0 mg). Subsequently, 3cycles of deaeration and replacement with nitrogen and then 3 cycles ofdeaeration and replacement with hydrogen were carried out, followed bystirring overnight at room temperature. Once the palladium catalyst wasremoved through Celite filtration, 10% palladium-carbon (50.0 mg) wasadded again. Then, the mixture was subjected to 3 cycles of deaerationand replacement with nitrogen and 3 cycles of deaeration and replacementwith hydrogen, followed by stirring overnight at room temperature. Aftercompletion of the reaction, the reaction mixture was filtrated throughCelite filtration and the filtrate was then subjected to solventdistillation under reduced pressure. Subsequently, the residue was driedunder vacuum, thereby obtaining the subject compound (145.9 mg) as ayellow liquid.

MS(FAB, Pos.) m/z=185[M+H]⁺

Example 31-2 Synthesis of(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-(4-dipropylaminopiperidin-1-yl)-methanone[Compound No. 31]

The compound (31.2 mg) obtained in Example 2-2, DCC (30.0 mg), and HOBt(20.5 mg) were dissolved in DMF (0.5 ml) and stirred for 15 minutes.Then, the compound (25.6 mg) obtained in Example 31-1 was added,followed by stirring at room temperature for 5 hours. After completionof the reaction, the solvent was distilled off under reduced pressureand the residue was then dissolved in 1 mol/l hydrochloric acid,followed by removing impurities with chloroform. The resulting aqueouslayer was added with chloroform and then added with 1 mol/l sodiumhydroxide to make the layer alkaline, followed by extraction withchloroform. The extract was washed with saturated saline solution andthen dried with anhydrous sodium sulfate. After filtration, the solventwas distilled off under reduced pressure and the residue was thenpurified through silica gel column chromatography (chloroform/methanol).Subsequently, the purified product was treated with hydrochloric acid,thereby obtaining hydrochloride (9.9 mg) of the subject compound as awhite solid.

MS(FAB, Pos.) m/z=478[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.93(6H, t, J=7.3 Hz), 1.63–1.74(6H, m),1.94–2.14(2H, br), 2.74–2.86(1H, br), 2.91–3.00(2H, br), 3.09–3.17(3H,m), 3.49–3.60(2H, m), 3.73(2H, s), 4.18(4H, s), 4.54–4.63(1H, br),7.28(2H, d, J=8.2 Hz), 7.40(2H, d, J=8.2 Hz), 7.56(2H, s).

Production Example 32 Synthesis of(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-(4-propylpiperazin-1-yl)-methanone[Compound No. 32] Example 32-1 Synthesis of4-(4-{[bis-(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzoyl)-piperazin-1-carboxylicacid t-butyl ester

The compound (500 mg) obtained in Example 2-2 was dissolved in DMF (10ml) and added with WSCI hydrochloride (257 mg), HOBt (181 mg), and 1-Bocpiperazine (manufactured by Aldrich Corporation) (249 mg), followed bystirring at room temperature for 3 days. After completion of thereaction, the solvent was distilled off and the residue was thendissolved in chloroform for extraction, followed by washing withdistilled water, a 1 mol/l sodium hydroxide aqueous solution, andsaturated saline solution. The resulting organic layer was dried withanhydrous sodium sulfate. The solvent was distilled off and the residuewas then purified through silica gel column chromatography(chloroform/methanol/water), thereby obtaining the subject compound (111mg) as a yellow oily substance.

MS(FAB, Pos.): m/z=480[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=1.40(9H, s), 3.25–3.44(8H, m), 3.54(2H,s), 3.63(4H, s), 7.02(4H, s), 7.34(2H, d, J=8.2 Hz), 7.47(2H, d, J=8.2Hz).

Example 32-2 Synthesis of(4-{[bis-(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-piperazin-1-yl-methanone

The compound (111 mg) obtained in Example 32-1 was dissolved inanhydrous methanol (1.0 ml) and then added with a 4 mol/l hydrogenchloride/dioxane solution (3.0 ml) and stirred at room temperature for 1hour. After completion of the reaction, the solvent was distilled offand the residue was added with a 1 mol/l sodium hydroxide aqueoussolution, followed by washing with dichloromethane. The aqueous layerwas evaporated to dryness, followed by distilling azeotropically withchloroform. Consequently, the subject compound (48.5 mg) was obtained asa yellow oily substance.

MS(FAB, Pos.): m/z=380[M+H]⁺

Example 32-3 Synthesis of(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-(4-propylpiperazin-1-yl)-methanone[Compound No. 32]

The compound (48.8 mg) obtained in Example 32-2 was dissolved inanhydrous methanol (1.0 ml) and then added with sodium cyanoborohydride(16.2 mg), trimethyl orthoformate (21.1 μl), propionaldehyde (13.9 μl),followed by stirring overnight at room temperature under a nitrogenatmosphere. After completion of the reaction, the solvent was distilledoff and the residue was then dissolved in chloroform. A saturatedaqueous sodium bicarbonate solution was added to the solution, followedby stirring. The resultant solution was subjected to extraction withchloroform and washed with a saturated aqueous sodium bicarbonatesolution and saturated saline solution, and then the organic layer wasdried with anhydrous sodium sulfate. The solvent was distilled off andthe residue was then treated with hydrochloric acid. Subsequently, thetreated product was purified through silica gel column chromatography(chloroform/methanol/water), thereby obtaining hydrochloride (33.2 mg)of the subject compound as a white solid.

MS(FAB, Pos.): m/z=422[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.93(3H, s), 1.68–1.74(2H, m),3.03–3.08(4H, m), 3.39–3.62(6H, m), 3.74(2H, s), 4.17(4H, s), 7.32(2H,d, J=8.2 Hz), 7.42(2H, d, J=8.2 Hz), 7.56(4H, s).

Production Example 33 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(3-dipropylaminomethylphenyl)-benzamide[Compound No. 33) Example 33-1 Synthesis of(3-nitro-benzyl)dipropylamine

Commercially available 3-nitrobenzylamine hydrochloride (manufactured byTokyo Kasei Kogyo Co., Ltd.) (1.62 g) was suspended in chloroform (15ml) and then added with a 1 mol/l sodium hydroxide aqueous solution (15ml). The aqueous layer was extracted with chloroform and the extract wasthen dried with anhydrous magnesium sulfate, followed by distilling thesolvent off. Subsequently, the residue was dissolved in anhydrousmethanol (25 ml) and then added with propionaldehyde (1.49 ml),trimethyl orthoformate (2.82 ml), and sodium cyanoborohydride (1.62 g),followed by stirring at room temperature for 2 hours. After completionof the reaction, the solvent was distilled off. Then, the residue wasadded with water and extracted with chloroform. The extract was driedwith anhydrous magnesium sulfate and the solvent was then distilled off.The residue was purified through silica gel column chromatography(hexane/ethyl acetate), thereby obtaining the subject compound (608.1mg) as a yellow oily substance.

MS(FAB, Pos.): m/z=237[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.87(6H, t, J=7.3 Hz), 1.48(4H, sext., J=7.3Hz), 2.39(4H, t, J=7.1 Hz), 3.63(2H, s), 7.46(1H, t, J=8.1 Hz), 7.69(1H,d, J=7.6 Hz), 8.08(1H, d, J=5.9 Hz), 8.22(1H, s).

Example 33-2 Synthesis of 3-dipropylaminomethylaniline

The compound (595 mg) obtained in Example 33-1 was dissolved in methanol(6.0 ml) and THF (3.0 ml). The solution was added with activated carbon(59.0 mg) and iron trichloride hexahydrate (manufactured by KantoKagaku) (5.90 mg), followed by thermal reflux for 30 minutes. Afterhaving been cooled to room temperature, the mixture was added withhydrazine monohydrate (0.43 ml) and then subjected to thermal reflux for24 hours. After completion of the reaction, the mixture was subjected toCelite filtration and the solvent was then distilled off. The residuewas added with water and then extracted with chloroform. The extract wasdried with anhydrous magnesium sulfate and then solvent was distilledoff. Subsequently, the residue was purified through silica gel columnchromatography (chloroform/methanol), thereby obtaining the subjectcompound (343.9 mg) as a yellow oily substance.

MS(FAB, Pos.): m/z=207[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.90(6H, t, J=7.3 Hz), 1.92–1.94(4H, m),2.89(4H, t, J=8.2 Hz), 3.72(2H, br), 3.78(2H, br), 6.63(1H, dd, J=1.7,8.0 Hz), 6.72(1H, d, J=7.3 Hz), 6.90(1H, brs), 7.11(1H, t, J=7.8 Hz).

Example 33-3 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(3-dipropylaminomethylphenyl)-benzamide[Compound No. 33]

The compound (51.6 mg) obtained in Example 33-2, the compound (117 mg)obtained in Example 2-2, and HOBt (50.0 mg) were dissolved in anhydrousDMF (2.5 ml). Then, the solution was added with PS-carbodiimide(manufactured by Argonaut Technologies, Inc.) (373.1 mg), followed bystirring at room temperature for 17 hours. After completion of thereaction, the mixture was filtrated and the solvent was then distilledoff. The residue was dissolved in chloroform and washed with a 1 mol/lsodium hydroxide aqueous solution and saturated saline solution. Theresidue was dried with anhydrous magnesium sulfate and the solvent wasdistilled off, followed by treatment with hydrochloric acid. The residuewas purified through silica gel column chromatography(chloroform/methanol/water), thereby obtaining hydrochloride (18.5 mg)of the subject compound as a white solid.

MS(FAB, Pos.): m/z=500[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.88(6H, t, J=7.3 Hz), 1.73(4H, sept., J=7.2Hz), 2.94–2.96(4H, br), 3.76(2H, s), 4.14(4H, s), 4.30(2H, brs),7.36(1H, d, J=7.8 Hz), 7.45(1H, t, J=7.9 Hz), 7.60(2H, d, J=2.7 Hz),7.62(4H, s), 7.75(1H, d, J=9.0 Hz), 7.92(2H, d, J=8.4 Hz), 8.05(1H, s),10.16(1H, br), 10.40(1H, s).

Production Example 34 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-{[(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-benzamide[Compound No. 34] Example 34-1 Synthesis of(1H-imidazol-2-ylmethyl)-(4-nitrobenzyl)amine

Commercially available 4-nitrobenzylamine hydrochloride (manufactured byTokyo Kasei Kogyo Co., Ltd.) (647 mg) was suspended in chloroform (15ml). Then, the suspension was added with a 1 mol/l sodium hydroxideaqueous solution (10 ml). The aqueous layer was extracted withchloroform and the extract was then dried with anhydrous magnesiumsulfate, followed by distilling the solvent off. Subsequently, theresidue was dissolved in anhydrous methanol (20 ml). The solution wasadded with 2-imidazole carboxaldehyde (495 mg) and trimethylorthoformate (1.13 ml), followed by stirring at room temperature for 15hours. After that, the solution was cooled with ice and added withsodium borohydride (389 mg), followed by stirring for 1 hour underice-cooling. The solvent was distilled off under reduced pressure andthe residue was added with water, followed by extraction withchloroform. The extract was dried with anhydrous magnesium sulfate andthe solvent was then distilled off, thereby obtaining the subjectcompound (733 mg) as a yellow oily substance.

MS(FAB, Pos.): m/z=233[M+H]⁺

Example 34-2 Synthesis of(1H-imidazol-2-ylmethyl)-(4-nitrobenzyl)carbamic acid t-butyl ester

The compound (733 mg) obtained in Example 34-1 was dissolved inchloroform (15 ml) and then added with di-t-butyl dicarbonate (1.51 g).After having been stirred at room temperature for 1 hour, the solutionwas concentrated and purified through silica gel column chromatography(chloroform/methanol), thereby obtaining the subject compound (993 mg)as a pale-yellow viscous liquid.

MS(FAB, Pos.): m/z=333[M+H]⁺

Example 34-3 Synthesis of(4-aminobenzyl)-(1H-imidazol-2-ylmethyl)carbamic acid t-butyl ester

The compound (325 mg) obtained in Example 34-2 was dissolved in ethanol(15 ml) and then cooled with ice. The solution was carefully added with10% palladium-carbon (Mitsuwa Chemicals Co., Ltd.) (300 mg), followed bystirring under a hydrogen atmosphere for 30 minutes. The solution wassubjected to Celite filtration and the filtrate was then concentrated,thereby obtaining the subject compound (233 mg) as a pale-red whitesolid.

MS(FAB, Pos.): m/z=303[M+H]⁺

Example 34-4 Synthesis of[4-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzoylamino)benzyl]-(1H-imidazol-2-ylmethyl)carbamicacid t-butyl ester

The compound (150 mg) obtained in Example 34-3 was dissolved in DMF (3.0ml) and then added with the compound (140 mg) synthesized in Example2-2. To the mixture solution, HOBt (79.0 mg) and PS-carbodiimide(manufactured by Argonaut Technologies, Inc.) (681 mg) were added,followed by stirring at room temperature for 18 hours. After completionof the reaction, PS-carbodiimide was filtrated and DMF in the filtratewas then distilled off. The residue was added with chloroform and washedwith a 1 mol/l sodium hydroxide aqueous solution and saturated salinesolution. The residue was brought into an anhydrous state usinganhydrous sodium sulfate and then concentrated. Subsequently, theconcentrated product was purified through column chromatography(chloroform/methanol), thereby obtaining the subject compound (105 mg)as a white solid.

MS(FAB, Pos.): m/z=596[M+H]⁺

Example 34-5 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-{[(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-benzamide[Compound No. 34]

The compound (105 mg) obtained in Example 34-4 was dissolved in methanol(10 ml) and then added with 1 mol/l hydrochloric acid (2.0 ml), followedby stirring at room temperature for 5 minutes. The solution wasconcentrated and dried, and then purified through column chromatography(chloroform/methanol), thereby obtaining hydrochloride (64 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=496[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=3.78(2H, s), 4.15(4H, s), 4.29(2H, s),4.53(2H, s), 7.56(2H, d, J=8.7 Hz), 7.62(2H, d, J=8.2 Hz), 7.62(4H, s),7.73(2H, s), 7.85(2H, d, J=8.7 Hz), 7.92(2H, d, J=8.2 Hz), 10.3(3H, s),14.6–14.9(4H, brs).

Production Example 35 Synthesis of[4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxy)-benzyl]-dipropylamine[Compound No. 35] Example 35-1 Synthesis of4-{[N-Boc(N-1H-imidazol-2-ylmethyl)amino]methyl}benzoic acid methylester

The compound (2.00 g) obtained in Example 1-1 was dissolved in methanol(40 ml) and then added with WSCI hydrochloride (1.74 g) and HOBt (1.22g), followed by stirring overnight at room temperature. After completionof the reaction, the solvent was distilled off and the residue was thendissolved in chloroform. The solution was added with a saturated aqueoussodium bicarbonate solution and stirred, followed by extraction withchloroform. The extract was washed with a saturated aqueous sodiumbicarbonate solution, a saturated aqueous ammonium chloride solution,and saturated saline solution. The organic layer was dried withanhydrous sodium sulfate. The solvent was distilled off, therebyobtaining the subject compound (2.42 g) as a colorless solid.

MS(FAB, Pos.): m/z=346[M+H]⁺

Example 35-2 Synthesis of4-{[N-Boc(N-1H-imidazol-2-ylmethyl)amino]methyl}benzyl alcohol

The compound (2.42 g) obtained in Example 35-1 was dissolved inanhydrous THF (5.0 ml) and then added with lithium aluminum hydride (799mg) in an ice bath, followed by stirring at room temperature for 2hours. After completion of the reaction, the solution was added withmethanol and then with an aqueous potassium sodium tartrate solution,followed by stirring. The solution was extracted with chloroform,followed by washing with saturated saline solution. Subsequently, theorganic layer was dried with anhydrous sodium sulfate. The solvent wasdistilled off and the residue was then purified through silica gelcolumn chromatography (chloroform/methanol), thereby obtaining thesubject compound (1.76 g) as a colorless solid.

MS(FAB, Pos.): m/z=318[M+H]⁺

Example 35-3 Synthesis of 4-(N,N-dipropylamino)methylphenol

In methanol, 4-hydroxybenzaldehyde (manufactured by Tokyo Kasei KogyoCo., Ltd.) (1.00 g) was dissolved. Then, the solution was added withdipropylamine (1.24 ml), trimethyl orthoformate (1.0 ml), and aceticacid (500 μl) and stirred at room temperature for 15 minutes. Thesolution was cooled to 0° C. and added with sodium cyanoborohydride (773mg), followed by stirring for 6 hours at room temperature. Aftercompletion of the reaction, the solvent was distilled off under reducedpressure and the residue was then dissolved in chloroform, followed bythe addition of water. The solution was adjusted to about pH 7 with a 1mol/l sodium hydroxide aqueous solution and then subjected to extractionwith chloroform. The resulting organic layer was washed with saturatedsaline solution and then dried with anhydrous sodium sulfate. Afterfiltration, the solvent was distilled off under reduced pressure and theresidue was then purified through silica gel column chromatography(chloroform/methanol), thereby obtaining the subject compound (76.8 mg)as a pale-yellow solid.

MS(FAB, Pos.): m/z=208[M+l]⁺

Example 35-4 Synthesis of[4-(4-{[N-Boc(N-1H-imidazol-2-ylmethyl)amino]methyl}benzyloxy)benzyl]dipropylamine

The compound (107 mg) obtained in Example 35-2 was dissolved in THF (2.0ml) and then added with the compound (76.8 mg) obtained in Example 35-3,triphenylphosphine (177 mg) and diethylazodicarboxylate (manufactured byTokyo Kasei Kogyo Co., Ltd.) (305 μl), followed by stirring overnight atroom temperature. After completion of the reaction, the solvent wasdistilled off and the residue was then dissolved in chloroform toextract. The extract was washed with saturated saline solution and theorganic layer was then dried with anhydrous sodium sulfate. The solventwas distilled off and the residue was then purified through silica gelcolumn chromatography (chloroform/methanol), thereby obtaining thesubject compound (28.4 mg) as a yellow oily substance.

MS(FAB, Pos.): m/z=507[M+H]⁺

Example 35-5 Synthesis of[4-(4-{[N-(1H-imidazol-2-ylmethyl)amino]methyl}benzyloxy)benzyl]dipropylamine

The compound (28.4 mg) obtained in Example 35-4 was dissolved inanhydrous methanol (1.0 ml) and then added with a 4 mol/l hydrogenchloride/dioxane solution (1.00 ml), followed by stirring at roomtemperature for 2 hours. After completion of the reaction, the solventwas distilled off. Then, the residue was added with a 1 mol/l sodiumhydroxide aqueous solution and subjected to extraction with chloroform.The extract was washed with distilled water and saturated salinesolution and the organic layer was then dried with anhydrous sodiumsulfate. Subsequently, the solvent was distilled off, thereby obtainingthe subjected compound (20.4 mg) as a yellow oily substance.

MS(FAB, Pos.): m/z=407[M+H]⁺

Example 35-6 Synthesis of[4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxy)-benzyl]-dipropylamine[Compound No. 35]

The compound (20.4 mg) obtained in Example 35-5 was dissolved inanhydrous methanol (2.0 ml) and added with sodium cyanoborohydride (9.50mg), acetic acid (2.0 ml), and 2-imidazole carboxaldehyde (9.60 mg),followed by stirring at room temperature under a nitrogen atmosphere for6.5 hours and a half. After completion of the reaction, the solvent wasdistilled off. The residue was dissolved in chloroform and added with asaturated aqueous sodium bicarbonate solution, followed by stirring. Thesolution was subjected to extraction with chloroform and the extract wasthen washed with a saturated aqueous sodium bicarbonate solution andsaturated saline solution. Subsequently, the organic layer was driedwith anhydrous sodium sulfate. The solvent was distilled off, and theresidue was treated with hydrochloric acid and then purified throughsilica gel column chromatography (chloroform/methanol/water), therebyobtaining hydrochloride (4.50 mg) of the subject compound as a whitesolid.

MS(FAB, Pos.): m/z=487[M+H]⁺

Production Example 36 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-naphtalene-1-carboxylicacid (4-dipropylaminomethylphenyl)-amide [Compound No. 36] Example 36-1Synthesis of methyl 4-bromomethyl-1-naphthalene carboxylic acid

Commercially available 4-methyl-1-naphthalene carboxylic acid(manufactured by Tokyo Kasei Kogyo Co., Ltd.) (251 mg) was dissolved inmethanol (7.5 ml) and then aerated under ice-cooling with hydrogenchloride gas for 5 minutes. After that, the solution was stirred at roomtemperature for 19 hours and the solvent was then distilled off. Theresidue was dissolved in chloroform and then washed with a 1 mol/lsodium hydroxide aqueous solution. After the solution had been driedwith anhydrous sodium sulfate, the solvent was then distilled off. Theresidue was dissolved in carbon tetrachloride (8.0 ml) and then addedwith N-bromo succinimide (253 mg) and azobisisobutyronitrile (22.1 mg),followed by stirring at 70° C. for 6 hours. After completion of thereaction, the solid was removed through glass filter, followed byconcentration. The residue was dissolved in chloroform and then washedwith a 1 mol/l sodium hydroxide aqueous solution and saturated salinesolution. The solution was dried with anhydrous sodium sulfate and thesolvent was then distilled off. The residue was dried under reducedpressure, thereby obtaining the subject compound (364 mg) as apale-yellow oily substance.

MS(FAB, Pos.): m/z=279, 281[M+H]⁺

¹H-NMR(60 MHz, CDCl₃): δ=3.94(3H, s), 4.86(3H, s), 7.35–7.68(3H, m),7.88–8.21(2H, m), 8.66–8.89(1H, m).

Example 36-2 Synthesis of methyl-4-aminomethyl-1-naphthalene carboxylicacid

The compound (328 mg) obtained in Example 36-1 was dissolved in DMF (7.2ml), added with potassium phthalimide (359 mg), and stirred at roomtemperature for 12 hours. After completion of the reaction, the solventwas distilled off and the residue was then dissolved in chloroform,followed by washing with distilled water, a 1 mol/l sodium hydroxideaqueous solution, and saturated saline solution. The solution was driedwith anhydrous sodium sulfate, and the solvent was distilled off, andthe residue was then purified through silica gel column chromatography(hexane/ethyl acetate), thereby obtaining a white solid (281 mg).Subsequently, the solid (1.50 g) was dissolved in methanol (30 ml) andthen added with hydrazine monohydrate (7.5 ml), followed by heating upto 60° C. Methanol (30 ml) was added further to the solution and thewhole was stirred continuously for one hour at 60° C. After completionof the reaction, the solvent was distilled off and the residue wasdissolved in chloroform. The solution was washed with distilled waterand saturated saline solution and dried with anhydrous sodium sulfate.The solvent was distilled off and the residue was then dried undervacuum, thereby obtaining the subject compound (789 mg) as a pale-yellowsolid.

MS(FAB, Pos.): m/z=216[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=4.00(3H, s), 4.39(2H, s), 7.55(1H, d, J=7.6Hz), 7.57–7.65(2H, m), 8.11(1H, d, J=8.3 Hz), 8.15(1H, d, J=7.3 Hz),8.97(1H, d, J=8.5 Hz).

Example 36-3 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}naphthalene-1-carboxylicacid methyl ester

The compound (390 mg) obtained in Example 36-2 was dissolved by theaddition of anhydrous methanol (20 ml), and the solution was added withimidazole-2-carboxaldehyde (453 mg) and sodium cyanoborohydride (341mg), and adjusted to pH 5 by the addition of acetic acid (0.5 ml),followed by stirring for 18 hours. After completion of the reaction, themethanol was distilled off and the residue was then added with 1 mol/lsodium hydroxide (20 ml), followed by extraction with chloroform. Theorganic layer was washed with saturated saline solution and then driedwith anhydrous magnesium sulfate. After that, the solvent was distilledoff and the residue was then dried, thereby obtaining the subjectcompound (680 mg) as a white solid.

MS(FAB, Pos.): m/z=376[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=3.49(4H, s), 4.00(3H, s), 4.14(2H, s),7.06(4H, s), 7.51–7.64(3H, m), 8.06(1H, d, J=7.6 Hz), 8.30(1H, d, J=7.8Hz), 8.90(1H, d, J=7.8 Hz).

Example 36-4 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}naphthalene-1-carboxylicacid

The compound (675 mg) obtained in Example 36-3 was added with methanol(7.0 ml) and a 1 mol/l sodium hydroxide (7.0 ml), followed by stirringfor 1 hour. After completion of the reaction, 1 mol/l hydrochloric acid(8.0 ml) was added to adjust the solution to pH 4. Then, the solvent wasdistilled off and the residue was washed with methanol, followed bydrying. Consequently, the subject compound (677 mg) was obtained as awhite solid.

MS(FAB, Pos.): m/z=362[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=4.12(4H, s), 4.17(2H, s), 7.30(4H, s),7.58–7.66(3H, m), 8.02(1H, d, J=7.5 Hz), 8.07(1H, d, J=7.3 Hz), 8.78(1H,d, J=8.1 Hz).

Example 36-5 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-naphtalene-1-carboxylicacid (4-dipropylaminomethylphenyl)-amide [Compound No. 36]

The compound (130 mg) obtained in Example 36-4 was dissolved in DMF (3.0ml) and then added with DCC (60.0 mg) and HOBt (40.0 mg), followed bystirring at room temperature for 2 hours. The compound (50.0 mg)obtained in Example 19-2 was added to the solution at room temperature,and the whole was stirred overnight. After completion of the reaction,insoluble matter was removed from the solution through a G4 glass filterand the solvent was distilled off. The residue was dissolved inchloroform and then washed with 1 mol/l hydrochloric acid. The organiclayer was added with hydrochloric acid to separate the solution intolayers. Then, the aqueous layer was added with a sodium hydroxideaqueous solution to adjust it to pH 12. The aqueous layer was subjectedto extraction with chloroform, and the organic layer was dried withanhydrous sodium sulfate. Then, the solvent was distilled off.Subsequently, the residue was treated with hydrochloric acid and thenpurified through silica gel column chromatography(chloroform/methanol/water) thereby obtaining hydrochloride (17.4 mg) ofthe subject compound as a white foamed compound.

MS(FAB, Pos.): m/z=550[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.88(6H, t, J=7.3 Hz), 1.73(4H, br),2.92(4H, br), 4.20(4H, br), 4.27(2H, br), 7.47(4H, s), 7.59(4H, m)7.67(1H, d, J=7.2 Hz), 7.80(1H, d, J=7.3 Hz), 7.89(2H, d, J=8.5 Hz),8.13(2H, m), 10.44(1H, br), 10.74(1H, br).

Production Example 37 Synthesis of(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-[4-(1-propylbutyl)-piperazin-1-yl]-methanone[Compound No. 37] Example 37-1 Synthesis of(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-[4-(1-propylbutyl)-piperazin-1-yl]-methanone[Compound No. 37]

The compound (57.7 mg) obtained in Example 32-2 was dissolved inmethanol (1.73 ml) and then added with 4-heptanone (manufactured byTokyo Kasei Kogyo Co., Ltd.) (30.7 μl), sodium cyanoborohydride (13.8mg), and triethylamine (76.5 μl). The solution was adjusted to pH 5 withacetic acid and stirred at room temperature for 7 days. The reactionsolution was added with a 1 mol/l sodium hydroxide aqueous solution andthen the whole was separated and extracted with chloroform. The organiclayer was dried with anhydrous sodium sulfate. The solvent was distilledoff and the residue was then purified through silica gel columnchromatography (chloroform/methanol) and treated with hydrochloric acid,thereby obtaining hydrochloride (27.7 mg) of the subject compound as apale-yellow solid.

MS(FAB, Pos.): m/z=478[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.86(6H, t, J=7.1 Hz), 1.21–1.82(12H, m),3.04–3.55(5H, m), 3.74(2H, s), 4.16(4H, s), 7.35(2H, d, J=8.3 Hz),7.41(2H, d, J=8.3 Hz), 7.57(4H, s).

Production Example 38 Synthesis of(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-(4-cyclohexylpiperazin-1-yl)-methanone[Compound No. 38] Example 38-1 Synthesis of(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-(4-cyclohexylpiperazin-1-yl)-methanone[Compound No. 38]

The compound (57.7 mg) obtained in Example 32-3 was dissolved inmethanol (1.73 ml) and then added with cyclohexanone (21.6 mg), sodiumcyanoborohydride (13.8 mg), and triethylamine (76.5 μl). The solutionwas adjusted to pH 5 with acetic acid and stirred at room temperaturefor 7 days. The reaction solution was added with a 1 mol/l sodiumhydroxide aqueous solution and then the whole was separated andextracted with chloroform. The organic layer was dried with anhydroussodium sulfate. The solvent was distilled off and the residue was thenpurified through silica gel column chromatography (chloroform/methanol)and treated with hydrochloric acid, thereby obtaining hydrochloride (7.9mg) of the subject compound as a pale-yellow solid.

MS(FAB, Pos.): m/z=462[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=1.00–2.18(15H, m), 3.02–3.16(4H, m),3.71(2H, s), 4.13(4H, s), 7.33(2H, d, J=8.1 Hz), 7.45(2H, d, J=8.1 Hz),7.56(4H, s).

Production Example 39 Synthesis of(4-{[bis(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-(4-dipropylaminomethylphenyl)-amine[Compound No. 39] Example 39-1 Synthesis of2-{4-[(4-dipropylaminomethylphenylamino)methyl]benzyl}isoindole-1,3-dione

The compound (17.6 mg) obtained in Example 25-1, the compound (13.2 mg)obtained in Example 19-2, and sodium cyanoborohydride (8.7 mg) weredissolved in anhydrous methanol (1.0 ml). The solution was then adjustedto pH 5 with the addition of acetic acid, followed by stirring at roomtemperature for 4 hours. The reaction solution was added with distilledwater and then subjected to extraction with chloroform. After that, theorganic layer was washed with saturated saline solution and dried withanhydrous sodium sulfate. The solvent was distilled off and the residuewas then purified through silica gel preparative thin-layerchromatography (chloroform/methanol), thereby obtaining the subjectcompound (72.9 mg) as a yellow solid.

MS(FAB, Pos.): m/z=456[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): 2.35(4H, t, J=7.1 Hz), 3.46(2H, brs), 4.27(2H,s), 4.84(2H, s), 6.56(2H, d, J=8.5 Hz), 7.09(2H, d, J=8.3 Hz), 7.32(2H,d, J=8.1 Hz), 7.41(2H, d, J=8.1 Hz), 7.69–7.73(2H, m), 7.83–7.86(2H, m).

Example 39-2 Synthesis of(4-aminomethylbenzyl)-(4-dipropylaminomethylphenyl)-amine

The compound (521.6 mg) obtained in Example 39-1 was dissolved inmethanol (15 ml) and added with hydrazine monohydrate (0.11 ml),followed by stirring at 60° C. for 1.5 hours. The reaction solution wasadded with a 1 mol/l sodium hydroxide aqueous solution and thensubjected to extraction with chloroform. Subsequently, the organic layerwas washed with saturated saline solution and then dried with anhydroussodium sulfate. After the solvent had been distilled off, the subjectcompound (372 mg) was obtained as a yellow solid.

MS(FAB, Pos.): m/z=326[M+H]⁺

Example 39-3 Synthesis of(4-{[bis(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-(4-dipropylaminomethylphenyl)-amine[Compound No. 39]

The compound (57.3 mg) obtained in Example 39-2 was dissolved inmethanol (2.5 ml). The solution was added with 1-methyl-2-imidazolecarboxaldehyde (158 mg) and then added with sodium cyanoborohydride(68.4 mg). The reaction solution was adjusted to pH 5 by the addition ofacetic acid, followed by stirring for 17 hours at room temperature.Then, the reaction solution was added with a 1 mol/l sodium hydroxideaqueous solution and then subjected to extraction with chloroform. Afterthat, the organic layer was washed with saturated saline solution andthen dried with anhydrous sodium sulfate. After the solvent had beendistilled off, a 10% hydrogen chloride/methanol solution was added tothe residue, and the solvent was then distilled off. The residueobtained was purified through silica gel column chromatography(chloroform/methanol/water), thereby obtaining the subject compound(55.2 mg) as a yellow solid.

MS(FAB, Pos.): m/z=514[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.85(6H, t, J=7.3 Hz), 1.65(4H, m), 2.87(4H,m), 3.68(2H, brs), 3.70(6H, s), 4.09(2H, brs), 4.10(4H, brs), 4.22(2H,brs), 6.58(2H, d, J=8.7 Hz), 7.21(2H, d, J=8.7 Hz), 7.24(4H, s),7.47–7.51(4H, m).

Production Example 40 Synthesis of4-{[bis(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminobutyl)-benzamide[Compound No. 40] Example 40-1 Synthesis of4-{[bis(1-methyl-1H-imidazol-2-ylmethyl)amino]methyl}-benzoic acid

Commercially available amino methylbenzoic acid methyl ester(manufactured by Tokyo Kasei Kogyo Co., Ltd.) (278 mg) was dissolved inmethanol (9 ml). Then, the solution was added with 1-methyl-2-imidazolecarboxaldehyde (manufactured by Aldrich Corporation) (407 mg) and sodiumcyanoborohydride (317 mg), and then adjusted to about pH 5 with aceticacid, followed by stirring at room temperature for 3 days. Aftercompletion of the reaction, the solvent was distilled off and theresidue was then dissolved in chloroform, followed by washing with a 1mol/l sodium hydroxide solution. The solution was dried with anhydroussodium sulfate, and the solvent was distilled off. Subsequently, theresidue was dissolved in methanol (6.0 ml) and then added with 1 mol/lsodium hydroxide, followed by stirring at room temperature for 6 hours.After completion of the reaction, 1 mol/l hydrochloric acid (6.0 ml) wasadded and the solvent was distilled off. After that, ethanol was addedto remove insoluble matter, the solvent was distilled off, and theresidue was then dried, thereby obtaining the subject compound (519 mg)as a pale-yellow foamy substance.

MS(FAB, Pos.): m/z=340[M+H]⁺

Example 40-2 Synthesis of4-{[bis(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminobutyl)-benzamide[Compound No. 40]

The compound (75.0 mg) obtained in Example 40-1 was dissolved in DMF(2.0 ml) and then added with DCC (46.0 mg) and HOBt (36.0 mg), followedby stirring for 6 hours. A solution of the compound (76.0 mg) obtainedin Example 1-2 in DMF was added to the reaction system and then thewhole was stirred for 15 hours. After completion of the reaction, DMFwas distilled off and the residue was then dissolved in chloroform,followed by extraction with 1 mol/l hydrochloric acid. The aqueous layerwas added with a 1 mol/l sodium hydroxide aqueous solution and thenextracted with chloroform. The extract was dried with anhydrousmagnesium sulfate and the solvent was then distilled off, followed bytreating with hydrochloric acid. Subsequently, the treated product waspurified through silica gel column chromatography(chloroform/methanol/water), thereby obtaining hydrochloride (23.9 mg)of the subject compound as a white solid.

MS(FAB, Pos.): m/z=494[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.89(6H, t, J=7.4 Hz), 1.22–1.70(8H, m),2.99(4H, t, J=8.2 Hz), 3.07(2H, t, J=7.0 Hz), 3.72(6H, s), 3.78(2H, s),4.09(4H, s), 7.39(2H, d, J=8.4 Hz), 7.49(4H, d, J=8.1 Hz), 7.76(2H, d,J=8.4 Hz).

Production Example 41 Synthesis of4-{[bis(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide[Compound No. 41] Example 41-1 Synthesis of4-{[bis(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide[Compound No. 41]

The compound (100 mg) obtained in Example 2-2 was dissolved in DMF (2.0ml) and then added with DCC (73.0 mg) and HOBt (36.0 mg), followed bystirring for 15 hours. A solution (2.0 ml) of the compound (73.0 mg)obtained in Example 19-2 in DMF was added to the reaction system andthen the whole was stirred for 24 hours. After completion of thereaction, DMF was distilled off and the residue was then dissolved inchloroform, followed by extraction with 1 mol/l hydrochloric acid. Theaqueous layer was added with a 1 mol/l sodium hydroxide aqueous solutionand then extracted with chloroform. The extract was dried with anhydrousmagnesium sulfate and the solvent was then distilled off, followed bytreating with hydrochloric acid. Subsequently, the treated product waspurified through silica gel column chromatography(chloroform/methanol/water), thereby obtaining hydrochloride (14.2 mg)of the subject compound as a white solid.

MS(FAB, Pos.): m/z=528[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.88(6H, t, J=7.3 Hz), 1.63–1.75(4H, m),2.96(4H, t, J=7.5 Hz), 3.72(6H, s), 3.82(2H, s), 4.09(4H, s), 4.29(2H,s), 7.45–7.53(8H, m), 7.85–7.91(4H, m), 10.43(1H, s).

Production Example 42 Synthesis of[4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzylamino)-butyl]-carbamicacid benzyl ester [Compound No. 42] Example 42-1 Synthesis of{4-[4-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)benzylamino]butyl}carbamicacid benzyl ester

In ethanol (40 ml), 1,4-diaminobutane (1.28 g) was dissolved and thenthe solution was cooled to 0° C., followed by the addition of a 2 mol/laqueous sodium acetate solution (10 ml) prepared in advance.Benzyloxylcarbonyl chloride (manufactured by Wako Pure ChemicalIndustries, Ltd.) (1.13 ml) and a 4 mol/l sodium hydroxide aqueoussolution (1.2 ml) were added in this order. After having been heated toroom temperature, the solution was stirred for 3 hours. Then, thesolution was concentrated and ethanol was then distilled off, followedby the addition of chloroform to carry out extraction. The extract wasdried with anhydrous sodium sulfate, and the solvent was distilled off.Then, the residue was added with the compound (151 mg) obtained inExample 25-1 and methanol (5.0 ml). Subsequently, the mixture was addedwith sodium cyanoborohydride (36 mg) and acetic acid (0.1 ml), followedby stirring at room temperature for 18 hours. After completion of thereaction, the solvent was distilled off, a 1 mol/l sodium hydroxideaqueous solution was added to the residue, and then the whole wasextracted with chloroform. The extract was dried with anhydrous sodiumsulfate and the solvent was then distilled off. After that, the residuewas purified through silica gel column chromatography(chloroform/methanol/water), thereby obtaining the subject compound (153mg) as a colorless viscous liquid.

MS(FAB, Pos.): m/z=472[M+H]⁺

Example 42-2 Synthesis of(4-benzyloxycarbonylaminobutyl)-[4-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)benzyl]-carbamicacid t-butyl ester

The compound (153 mg) obtained in Example 42-1 was dissolved inchloroform (15 ml) and then added with di-t-butyl dicarbonate (106 mg).After having been stirred at room temperature for 1 hour, the solutionwas concentrated and purified through silica gel column chromatography(chloroform/methanol), thereby obtaining the subject compound (173 mg)as a colorless viscous liquid.

MS(FAB, Pos.): m/z=572[M+H]⁺

Example 42-3 Synthesis of(4-aminomethylbenzyl)-(4-benzyloxycarbonylaminobutyl)-carbamic acidt-butyl ester

The compound (173 mg) obtained in Example 42-2 was added with a 40%methylamine/methanol solution (3.0 ml), followed by stirring at roomtemperature for 14 hours. After completion of the reaction, the solventwas distilled off and the residue was then added with a 1 mol/l sodiumhydroxide aqueous solution, followed by extraction with chloroform. Theextract was dried with anhydrous sodium sulfate. Subsequently, thesolvent was distilled off, thereby obtaining the subject compound (98.9mg) as a colorless viscous liquid.

MS(FAB, Pos.): m/z=442[M+H]⁺

Example 42-4 Synthesis of[4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzylamino)-butyl]-carbamicacid benzyl ester [Compound No. 42]

The compound (98.9 mg) obtained in Example 42-3 was dissolved inanhydrous methanol (5.0 ml) and then added with 2-imidazolecarboxaldehyde (49.0 mg), sodium cyanoborohydride (28.0 mg), and aceticacid (0.1 ml) in this order. The solution was stirred at roomtemperature for 15 hours and methanol was then distilled off, followedby the addition of a 1 mol/l sodium hydroxide aqueous solution. Thesolution was subjected to extraction with chloroform and the extract wasthen dried with anhydrous sodium sulfate, and the solvent was distilledoff. The residue was purified through silica gel column chromatography(chloroform/methanol/water) and then treated with hydrochloric acid,thereby obtaining hydrochloride (82.0 mg) of the subject compound as awhite solid.

MS(FAB, Pos.): m/z=502[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=1.41–1.44(2H, m), 1.59–1.64(2H, m), 2.80(2H,brs), 2.97–3.01(2H, m), 3.67(2H, s), 4.02–4.05(2H, m), 4.11(4H, s),5.00(2H, s), 7.29–7.38(5H, m), 7.44(2H, d, J=8.2 Hz), 7.49(2H, d, J=8.2Hz), 7.61(4H, s), 9.18(2H, brs), 14.69(3H, brs).

Production Example 43 Synthesis of(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-(4-dipropylaminomethylphenyl)-amine[Compound No. 43] Example 43-1 Synthesis of(4-dipropylaminomethylphenyl)-(4-{[(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-amine

The compound (63.1 mg) obtained in Example 39-2 was dissolved inmethanol (2.0 ml) and then added with 2-imidazole carboxaldehyde (17.9mg), followed by stirring at room temperature for 17 hours. After thesolvent had been distilled off, the residue was dried under vacuum andthen dissolved in methanol (2.5 ml). Subsequently, the solution wasadded with sodium borohydride (14.5 mg) and stirred at room temperaturefor 1 hour. The reaction solution was added with a saturated aqueousammonium chloride solution (4.0 ml) and stirred at room temperature for30 minutes. Then, the reaction solution was added with saturated salinesolution and subjected to extraction with chloroform, followed by dryingwith anhydrous sodium sulfate. After the solvent had been distilled off,the residue obtained was purified through silica gel columnchromatography (chloroform/acetone), thereby obtaining the subjectcompound (45.2 mg) as a yellow solid.

MS(FAB, Pos.): m/z=406[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=0.85(6H, t, J=7.3 Hz), 1.46(4H, tq, J=6.9, 7.3Hz), 2.34(4H, t, J=6.9 Hz), 3.44(2H, s), 3.80(2H, s), 3.93(2H, s),4.30(2H, brs), 6.58(2H, d, J=8.5 Hz), 6.99(2H, s), 7.11(2H, d, J=8.5Hz), 7.28 (2H, d, J=8.3 Hz), 7.34(2H, d, J=8.3 Hz).

Example 43-2 Synthesis of(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-(4-dipropylaminomethylphenyl)-amine[Compound No. 43]

The compound (199 mg) obtained in Example 43-1 was dissolved in methanol(6 ml) and then added with 2-imidazole carboxaldehyde (57.1 mg) andsodium cyanoborohydride (65.4 mg). The reaction solution was adjusted topH 5 with the addition of acetic acid, followed by stirring at roomtemperature for 14 hours. The reaction solution was added with a 1 mol/lsodium hydroxide aqueous solution and then extracted with chloroform.Then, the organic layer was washed with saturated saline solution anddried with anhydrous sodium sulfate. After the solvent had beendistilled off, the residue obtained was purified through silica gelcolumn chromatography (chloroform/methanol) and treated withhydrochloric acid, thereby obtaining hydrochloride (231 mg) of thesubject compound as a yellow solid.

MS(FAB, Pos.): m/z=486[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.85(6H, t, J=7.3 Hz), 1.65(4H, m), 2.88(4H,m), 3.64(2H, brs), 3.70(2H, brs), 4.09(4H, brs), 4.23(2H, brs), 6.59(2H,d, J=8.5 Hz), 7.19(2H, d, J=8.5 Hz), 7.24(2H, d, J=8.3 Hz), 7.29(2H, d,J=8.3 Hz), 7.55(4H, s).

Production Example 44 Synthesis of(4-dipropylaminomethylphenyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-amine[Compound No. 44] Example 44-1 Synthesis of(4-dipropylaminomethylphenyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-amine[Compound No. 44]

The compound (72.7 mg) obtained in Example 43-1 was dissolved inmethanol (3.5 ml) and then added with 1-methyl-2-imidazolecarboxaldehyde (28.6 mg) and sodium cyanoborohydride (22.8 mg). Thereaction solution was adjusted to pH 5 with the addition of acetic acid,followed by stirring at room temperature for 14 hours. The reactionsolution was added with a 1 mol/l sodium hydroxide aqueous solution andthen extracted with chloroform. Then, the organic layer was washed withsaturated saline solution and dried with anhydrous sodium sulfate. Afterthe solvent had been distilled off, the residue obtained was purifiedthrough silica gel column chromatography (chloroform/ethyl acetate) andtreated with hydrochloric acid, thereby obtaining hydrochloride (71.3mg) of the subject compound as a yellow solid.

MS(FAB, Pos.): m/z=500[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.84(6H, t, J=7.4 Hz), 1.69(4H, m), 2.84(4H,m), 3.57(2H, s), 3.65(3H, s), 4.07(2H, s), 4.08(2H, s), 4.16(2H, s),6.62(2H, d, J=8.1 Hz), 7.24(2H, d, J=8.1 Hz), 7.28(2H, d, J=8.3 Hz),7.34(2H, d, J=8.3 Hz), 7.48(1H, d, J=1.9 Hz), 7.49(1H, d, J=1.9 Hz),7.61(2H, s).

Production Example 45 Synthesis of(4-dipropylaminomethylphenyl)-(4-{[(1H-imidazol-2-ylmethyl)-(2H-pyrazol-3-ylmethyl)-amino]-methyl}-benzyl)-amine[Compound No. 45] Example 45-1 Synthesis of(4-dipropylaminomethylphenyl)-(4-{[(1H-imidazol-2-ylmethyl)-(2H-pyrazol-3-ylmethyl)-amino]-methyl}-benzyl)-amine[Compound No. 45]

The compound (72.0 mg) obtained in Example 43-1 was dissolved inmethanol (3.5 ml) and then added with pyrazole-3-carboxaldehyde (24.5mg) and sodium cyanoborohydride (35.9 mg). The reaction solution wasadjusted to pH 5 with the addition of acetic acid, followed by stirringat room temperature for 14 hours. The reaction solution was added with a1 mol/l sodium hydroxide aqueous solution and then extracted withchloroform. Then, the organic layer was washed with saturated salinesolution and dried with anhydrous sodium sulfate. After the solvent hadbeen distilled off, the residue obtained was purified through silica gelcolumn chromatography (chloroform/ethyl acetate) and treated withhydrochloric acid, thereby obtaining hydrochloride (52.3 mg) of thesubject compound as a yellow solid.

MS(FAB, Pos.): m/z=486[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.85(6H, t, J=7.5 Hz), 1.65(4H, m), 2.88(4H,m), 3.70(2H, brs), 3.78(2H, brs), 4.00(2H, brs), 4.10(2H, brs), 4.28(2H,brs), 6.34(1H, d, J=2.1 Hz), 6.65(2H, d, J=8.5 Hz), 7.21(2H, d, J=8.5Hz), 7.32(2H, d, J=8.3 Hz), 7.38(2H, d, J=8.3 Hz), 7.51(2H, s), 7.69(1H,d, J=2.1 Hz).

Production Example 46 Synthesis ofN-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2ylmethyl)-(6-methylpyridin-2-yl-methyl)-amino]-methyl}-benzamide[Compound No. 46] Example 46-1 Synthesis ofN-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2ylmethyl)-(6-methylpyridin-2-yl-methyl)-amino]-methyl}-benzamide[Compound No. 46]

The compound (44.3 mg) obtained in Example 1-4 was dissolved in methanol(1.0 ml) and then added with 6-methylpyridine-2-carboxaldehyde (20.7 mg)and sodium cyanoborohydride (10.7 mg). The solution was adjusted toabout pH 5 with acetic acid and then stirred at room temperature for 15hours. After completion of the reaction, the solvent was distilled offand the residue was then dissolved in chloroform, followed by washingwith a 1 mol/l sodium hydroxide aqueous solution and saturated salinesolution and drying with anhydrous sodium sulfate. The solvent wasdistilled off and the residue was then purified through silica gelcolumn chromatography (chloroform/methanol/water), thereby obtaining thesubject compound (9.9 mg) as a white solid.

MS(FAB, Pos.): m/z=491[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.90(6H, t, J=7.3 Hz), 1.51–1.73(8H, m),2.66(3H, s), 2.95–3.03(4H, m), 3.03–3.09(2H, m), 3.24–3.32(2H, m),3.79(2H, s), 4.00(2H, s), 4.10(2H, s), 7.33(1H, dd, J=7.5, 2.9 Hz),7.45(2H, d, J=8.3 Hz), 7.59(1H, d, J=7.5 Hz), 7.76(2H, d, J=8.3 Hz),7.78–7.81(1H, m).

Production Example 47 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(isoquinolin-3-ylmethyl)-amino]-methyl}-benzamide[Compound No. 47] Example 47-1 Synthesis of isoquinoline-3-aldehyde

Lithium aluminum hydride (229.4 mg) was suspended in anhydrous THF.Then, a solution of isoquinoline-3-carbocylic acid methyl ester (377.1mg) in THF was gradually added to the suspension, followed by thermalreflux for 4 hours. The reaction solution was cooled down and then addedwith ethyl acetate and methanol. After that, chloroform was added to thesolution and extraction was then carried out with 1 mol/l hydrochloricacid. The aqueous layer was adjusted to pH 12 or more with a 1 mol/lsodium hydroxide aqueous solution, followed by separation/extractionwith chloroform. The organic layer was dried with anhydrous sodiumsulfate and the solvent was then distilled off to obtain an alcoholproduct. The alcohol product was redissolved again in chloroform (16.5ml) and then added with manganese dioxide (chemically processed product:manufactured by Wako Pure Chemical Industries, Ltd., the same shallapply hereinafter) (2.33 g), followed by stirring at room temperaturefor 0.5 hour. The reaction solution was filtrated through Celite and thesolvent was then distilled off. Then the residue was purified throughsilica gel column chromatography (hexane/ethyl acetate), therebyobtaining the subject compound (20.2 mg) as an orange-color solid.

¹H-NMR(500 MHz, CDCl₃): δ=7.78–7.84(2H, m), 8.04(1H, d, J=8.1 Hz),8.09(1H, d, J=7.8 Hz), 8.41(1H, s), 9.39(1H, s), 10.3(1H, s).

Example 47-2 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[N-Boc-N-(1H-imidazol-2-ylmethyl)amino]methyl}-benzamide

The compound (1.34 g) obtained in Example 19-2 was dissolved in DMF (68ml). The solution was added with WSCI hydrochloride (4.73 g), HOBt (2.45g), and the compound (5.74 g) obtained in Example 1-1, followed bystirring at room temperature for 24 hours. After completion of thereaction, the solvent was distilled off and the residue was thenredissolved in chloroform, followed by washing with distilled water, a 1mol/l sodium hydroxide aqueous solution, and saturated saline solution.The solution was dried with anhydrous sodium sulfate, and the solventwas distilled off. The residue was recrystallized from ethylacetate/chloroform, thereby obtaining the subject compound (5.04 g) as awhite solid.

MS(FAB, Pos.): m/z=520[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.82(6H, t, J=7.3 Hz), 1.36(9H, brs),1.37–1.43(4H, sext., J=7.3 Hz), 2.32(4H, t, J=7.3 Hz), 3.47(2H, s),4.30–4.55(4H, br), 6.85(1H, s), 7.05(1H, s), 7.26(2H, d, J=8.5 Hz),7.32(2H, br), 7.70(2H, d, J=8.5 Hz), 7.91(2H, d, J=8.5 Hz), 10.18(1H,s), 11.8–12.0(1H, br).

Example 47-3 Synthesis ofN-(4-dipropylamino-phenyl)-4-{[(1H-imidazol-2-ylmethyl)amino]methyl}-benzamide

The compound (2.50 g) obtained in Example 47-2 was dissolved in methanol(25.0 ml) and then added with a 4 mol/l hydrogen chloride/dioxanesolution (50.0 ml), followed by stirring at room temperature for 1 hour.The reaction solvent was distilled off and the residue was then addedwith a 1 mol/l sodium hydroxide aqueous solution, followed byseparation/extraction with chloroform. The organic layer was dried withanhydrous sodium sulfate, and the solvent was then distilled off. Theresidue was dried under vacuum, thereby obtaining the subject compound(1.89 g) as a white solid.

Example 47-4 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(isoquinolin-3-ylmethyl)-amino]-methyl}-benzamide[Compound No. 47]

The compound (53.9 mg) obtained in Example 47-3 was dissolved inmethanol (2.0 ml) and then added with the compound (20.2 mg) obtained inExample 47-1 and sodium cyanoborohydride (12.8 mg). Then, the solutionwas adjusted to pH 5 with acetic acid and then stirred at roomtemperature for 14 hours. After completion of the reaction, a 1 mol/lsodium hydroxide aqueous solution was added to the reaction solution,followed by separation/extraction with chloroform. The organic layer wasdried with anhydrous sodium sulfate and the solvent was then distilledoff. The residue was purified through silica gel column chromatography(chloroform/ethyl acetate) and then treated with hydrochloric acid,thereby obtaining hydrochloride (10.1 mg) of the subject compound as awhite solid.

MS(FAB, Pos.): m/z=561[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.88(6H, t, J=7.3 Hz), 1.60–1.80(4H, m),2.96(4H, t, J=7.3 Hz), 3.86(2H, s), 4.14(2H, s), 4.17(2H, s), 4.28(2H,s), 7.48–7.60(6H, m), 7.80–7.94(5H, m), 8.04(1H, t, J=8.3 Hz), 8.14(1H,d, J=8.3 Hz), 8.25(1H, s), 8.39(1H, d, J=8.1 Hz), 9.64(1H, s).

Production Example 48 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 48] Example 48-1 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 48]

The compound (52.0 mg) obtained in Example 47-3 was dissolved inmethanol (1.6 ml) and then added with pyridine-2-aldehyde (15.9 mg) andsodium cyanoborohydride (15.6 mg). The solution was adjusted to pH 5with acetic acid and stirred at room temperature for 14 hours. Aftercompletion of the reaction, the reaction solution was added with a 1mol/l sodium hydroxide aqueous solution and then separated and extractedwith chloroform. The organic layer was dried with anhydrous sodiumsulfate. The solvent was distilled off and the residue was then purifiedthrough silica gel column chromatography (chloroform/methanol) andtreated with hydrochloric acid, thereby obtaining hydrochloride (15.2mg) of the subject compound as a pale-yellow solid.

MS(FAB, Pos.): m/z=511[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.88(6H, t, J=7.3 Hz), 1.60–1.80(4H, m),2.96(4H, t, J=7.3 Hz), 3.81(2H, s), 4.04(2H, s), 4.12(2H, s), 4.28(2H,s), 7.48–7.59(5H, m), 8.18(1H, t, J=8.3 Hz), 8.69(1H, d, J=4.4 Hz).

Production Example 49 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 49] Example 49-1 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 49]

The compound (52.0 mg) obtained in Example 47-3 was dissolved inmethanol (1.6 ml) and then added with 1-methylimidazol-2-aldehyde (16.4mg), and sodium cyanoborohydride (15.6 mg). The solution was adjusted topH 5 with acetic acid and stirred at room temperature for 14 hours.After completion of the reaction, the reaction solution was added with a1 mol/l sodium hydroxide aqueous solution and then separated andextracted with chloroform. The organic layer was dried with anhydroussodium sulfate. The solvent was distilled off and the residue was thenpurified through silica gel column chromatography (chloroform/methanol)and treated with hydrochloric acid, thereby obtaining hydrochloride(15.2 mg) of the subject compound as a pale-yellow solid.

MS(FAB, Pos.): m/z=514[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.88(6H, t, J=7.3 Hz), 1.60–1.80(4H, m),2.96(4H, t, J=7.1 Hz), 3.72(3H, s), 3.81(2H, s), 4.08(2H, s), 4.16(2H,s), 4.28(2H, s), 7.42–7.58(6H, m), 7.60(2H, s), 7.82–7.92(4H, m).

Production Example 50 Synthesis ofN-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N-methyl-N′,N′-dipropylbutane-1,4-diamine[Compound No. 50] Example 50-1 Synthesis ofN-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N-methyl-N′,N′-dipropylbutane-1,4-diamine[Compound No. 50]

The compound (150.7 mg) obtained in Example 25-5 was dissolved inmethanol (3.0 ml). Then, a 36% formaldehyde aqueous solution(manufactured by Kanto Kagaku) (50 μl) and sodium cyanoborohydride (36.2mg) were added to the solution in this order. After the reactionsolution was adjusted to pH 5 with acetic acid, the solution was stirredat room temperature for 17 hours. The reaction solution was added with a1 mol/l sodium hydroxide aqueous solution and then extracted withchloroform. Subsequently, the organic layer was washed with saturatedsaline solution and then dried with anhydrous sodium sulfate. After thesolvent had been distilled off, the residue obtained was purifiedthrough silica gel column chromatography (chloroform/ethyl acetate) andthen treated with hydrochloric acid, thereby obtaining hydrochloride(126.2 mg) of the subjected compound as a white solid.

MS(FAB, Pos.): m/z=466[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.92(6H, t, J=7.6 Hz), 1.63–1.68(6H, m),1.69–1.93(2H, m), 2.58(3H, brs), 2.98–3.01(6H, m), 3.06(2H, t, J=8.1Hz), 3.62(2H, s), 3.72(2H, s), 4.14(4H, s), 7.45(4H, s), 7.58(4H, s).

Example 51-1 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(6-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 51] Example 51-2 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(6-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 51]

The compound (104.9 mg) obtained in Example 47-3 was dissolved inmethanol (3.2 ml) and then added with 6-methylpyridine-2-carboxaldehyde(36.3 mg) and sodium cyanoborohydride (31.4 mg). Then, the solution wasadjusted to pH 5 with acetic acid and then stirred at room temperaturefor 14 hours. After completion of the reaction, a 1 mol/l sodiumhydroxide aqueous solution was added to the reaction solution, followedby separation/extraction with chloroform. The organic layer was driedwith anhydrous sodium sulfate and the solvent was then distilled off.The residue was purified through silica gel column chromatography(chloroform/ethyl acetate) and then treated with hydrochloric acid,thereby obtaining hydrochloride (75.9 mg) of the subject compound as awhite solid.

MS(FAB, Pos.): m/z=525[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.88(6H, t, J=7.3 Hz), 1.60–1.80(4H, m),2.74(3H, s), 2.88–3.00(4H, m), 3.84(2H, s), 4.12(2H, s), 4.17(2H, s),4.28(2H, s), 7.48–7.60(6H, m), 7.72(1H, d, J=8.1 Hz), 7.82–7.92(4H, m),7.96(1H, d, J=7.8 Hz), 8.34(1H, t, J=8.1 Hz).

Production Example 52 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(6-bromopyridin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 52] Example 52-1 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(6-bromopyridin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 52]

The compound (104.9 mg) obtained in Example 47-3 was dissolved inmethanol (3.2 ml) and then added with 6-bromopyridine-2-aldehyde (55.8mg) and sodium cyanoborohydride (31.4 mg). Then, the solution wasadjusted to pH 5 with acetic acid and then stirred at room temperaturefor 14 hours. After completion of the reaction, a 1 mol/l sodiumhydroxide aqueous solution was added to the reaction solution, followedby separation/extraction with chloroform. The organic layer was driedwith anhydrous sodium sulfate and the solvent was then distilled off.The residue was purified through silica gel column chromatography(chloroform/ethyl acetate) and then treated with hydrochloric acid,thereby obtaining hydrochloride (91.9 mg) of the subject compound as awhite solid.

MS(FAB, Pos.): m/z=590[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.88(6H, t, J=7.3 Hz), 1.60–1.80(4H, m),2.88–3.00(4H, m), 3.81(2H, s), 3.81(2H, s), 4.09(2H, s), 4.28(2H, s),7.50–7.62(8H, m), 7.75(1H, t, J=7.6 Hz), 7.88(2H, d, J=8.5 Hz), 7.95(2H,d, J=8.5 Hz).

Production Example 53 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(3-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 53] Example 53-1 Synthesis of 3-methyl-2-pyridine aldehyde

Commercially available 2,3-lutidine (5.00 g) was dissolved indichloromethane (50 ml) and the solution was cooled to 0° C. After that,the solution was added with meta-chloroperbenzoic acid (12.1 g) and thenstirred at room temperature for 2 hours. After completion of thereaction, the solution was added with dichloromethane and washed with a1 mol/l sodium hydroxide aqueous solution and saturated saline solution,followed by drying with anhydrous sodium sulfate. Then, the solvent wasdistilled off, thereby obtaining crude 2,3-lutidin-N-oxide (3.16 g). A2.00 g part thereof was dissolved in dichloromethane (40 ml) and thenthe solution was cooled to 0° C. Subsequently, the solution was addedwith trifluoroacetic anhydride (4.49 ml), followed by stirring at roomtemperature for 4 hours and then at 45° C. for 3 hours. After completionof the reaction, the solvent was distilled off and the residue wasdissolved in methanol (30 ml), followed by the addition of a sodiummethoxide/methanol solution until the pH of the solution would reachpH=10. After the solution had been stirred at room temperature for 1hour, the solvent was distilled off and extraction was then carried outwith dichloromethane. The extract was dried with anhydrous sodiumsulfate and the solvent was then distilled off, thereby obtaining3-methyl-2-hydroxymethylpyridine (1.30 g). A 605.3 mg part thereof wasdissolved in chloroform (30 ml) and then added with manganese dioxide(chemically processed product) (3.03 g), followed by stirring at 70° C.for 2 hours. After completion of the reaction, the catalyst was removedthrough Celite filtration and the solvent was then concentrated. Then,the residue was purified through silica gel column chromatography(chloroform/ethyl acetate), thereby obtaining the subject compound(419.8 mg) as a pale-orange colored liquid.

MS(FAB, Pos.): m/z=122[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=2.67(3H, s), 7.40(1H, dd, J=7.8, 4.6 Hz),7.64(1H, d, J=7.8 Hz), 8.67(1H, d, J=4.6 Hz), 10.2(1H, s).

Example 53-2 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(3-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 53]

The compound (104.9 mg) obtained in Example 47-3 was dissolved inmethanol (3.2 ml) and then added with the compound (36.3 mg) obtained inExample 53-1 and sodium cyanoborohydride (31.4 mg). Then, the solutionwas adjusted to pH 5 with acetic acid and then stirred at roomtemperature for 14 hours. After completion of the reaction, a 1 mol/lsodium hydroxide aqueous solution was added to the reaction solution,followed by separation/extraction with chloroform. The organic layer wasdried with anhydrous sodium sulfate and the solvent was then distilledoff. The residue was purified through silica gel column chromatography(chloroform/ethyl acetate) and then treated with hydrochloric acid,thereby obtaining hydrochloride (91.5 mg) of the subject compound as awhite solid.

MS(FAB, Pos.) m/z=525[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.88(6H, t, J=7.3 Hz), 1.60–1.80(4H, m),2.37(3H, s), 2.95(4H, t, J=7.1 Hz), 3.84(2H, s), 4.16(2H, s), 4.25(2H,s), 4.28(2H, s), 7.53(2H, d, J=8.5 Hz), 7.55(2H, d, J=8.3 Hz), 7.62(2H,s), 7.76(1H, dd, J=4.8, 7.6 Hz), 7.83(2H, d, J=8.5 Hz), 7.86(2H, d,J=8.3 Hz), 8.22(1H, d, J=7.6 Hz), 8.65(1H, d, J=4.9 Hz).

Production Example 54 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(quinolin-4-ylmethyl)-amino]-methyl}-benzamide[Compound No. 54] Example 54-1 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(quinolin-4-ylmethyl)-amino]-methyl}-benzamide[Compound No. 54]

The compound (104.9 mg) obtained in Example 47-3 was dissolved inmethanol (3.2 ml) and then added with quinoline-4-aldehyde (47.2 mg) andsodium cyanoborohydride (31.4 mg). Then, the solution was adjusted to pH5 with acetic acid and then stirred at room temperature for 14 hours.After completion of the reaction, a 1 mol/l sodium hydroxide aqueoussolution was added to the reaction solution, followed byseparation/extraction with chloroform. The organic layer was dried withanhydrous sodium sulfate and the solvent was then distilled off. Theresidue was purified through silica gel column chromatography(chloroform/ethyl acetate) and then treated with hydrochloric acid,thereby obtaining hydrochloride (76.4 mg) of the subject compound as awhite solid.

MS(FAB, Pos.): m/z=561[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.88(6H, t, J=7.3 Hz), 1.60–1.80(4H, m),2.95(4H, br), 3.92(2H, s), 4.17(2H, s), 4.28(2H, s), 4.41 (2H, s),7.48–7.60(6H, m), 7.82–7.96(5H, m), 8.02–8.28(3H, m), 8.40(1H, d, J=8.3Hz), 9.16(1H, d, J=5.4 Hz).

Production Example 55 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(quinolin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 55] Example 55-1 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(quinolin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 55]

The compound (81.2 mg) obtained in Example 47-3 was dissolved inmethanol (3.2 ml) and then added with quinoline-2-aldehyde (36.5 mg) andsodium cyanoborohydride (24.3 mg). Then, the solution was adjusted to pH5 with acetic acid and then stirred at room temperature for 14 hours.After completion of the reaction, a 1 mol/l sodium hydroxide aqueoussolution was added to the reaction solution, followed byseparation/extraction with chloroform. The organic layer was dried withanhydrous sodium sulfate and the solvent was then distilled off. Theresidue was purified through silica gel column chromatography(chloroform/ethyl acetate) and then treated with hydrochloric acid,thereby obtaining hydrochloride (77.8 mg) of the subject compound as awhite solid.

MS(FAB, Pos.): m/z=560[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.88(6H, t, J=7.3 Hz), 1.60–1.80(4H, m),2.96(4H, br), 3.88(2H, s), 4.03(2H, s), 4.18(2H, s), 4.28 (2H, s),7.50–7.61(6H, m), 7.70–8.04(7H, m), 8.13(1H, d, J=8.1 Hz), 8.20(1H, d,J=8.8 Hz), 8.70(1H, d, J=8.3 Hz).

Production Example 56 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 56] Example 56-1 Synthesis of 5-methyl-2-pyridine aldehyde

By the similar procedures as those of Example 53-1, except of using2,5-lutidine as a raw material, 5-methylpyridine-2-aldehyde (439.9 mg)was obtained.

MS(FAB, Pos.): m/z=122[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=2.46(3H, s), 7.67(1H, dd, J=7.9, 1.4 Hz),7.89(1H, d, J=7.9 Hz), 8.62(1H, d, J=1.4 Hz), 10.05(1H, s).

Example 56-2 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 56]

The compound (79.4 mg) obtained in Example 47-3 was dissolved inmethanol (2.4 ml) and then added with the compound (27.5 mg) obtained inExample 56-1 and sodium cyanoborohydride (23.8 mg). Then, the solutionwas adjusted to pH 5 with acetic acid and then stirred at roomtemperature for 14 hours. After completion of the reaction, a 1 mol/lsodium hydroxide aqueous solution was added to the reaction solution,followed by separation/extraction with chloroform. The organic layer wasdried with anhydrous sodium sulfate and the solvent was then distilledoff. The residue was purified through silica gel column chromatography(chloroform/ethyl acetate) and then treated with hydrochloric acid,thereby obtaining hydrochloride (63.0 mg) of the subject compound as awhite solid.

MS(FAB, Pos.): m/z=525[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.88(6H, t, J=7.3 Hz), 1.60–1.80(4H, m),2.44(3H, s), 2.95(4H, br), 3.80(2H, s), 4.13(2H, s), 4.16 (2H, s),4.28(2H, s), 7.53(2H, d, J=7.8 Hz), 7.55(2H, d, J=7.8 Hz), 7.58 (2H, s),7.86(4H, d, J=7.8 Hz), 7.95(1H, d, J=8.3 Hz), 8.30(1H, dd, J=1.5, 8.3Hz), 8.66(1H, d, J=1.5 Hz).

Production Example 57 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-3-ylmethyl)-amino]-methyl}-benzamide[Compound No. 57] Example 57-1 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-3-ylmethyl)-amino]-methyl}-benzamide[Compound No. 57]

The compound (100 mg) obtained in Example 47-3 was dissolved in methanol(5.0 ml) and added with pyridin-3-aldehyde (manufactured by Tokyo KaseiKogyo Co., Ltd.) (44.8 μl), followed by the addition of sodiumcyanoborohydride (44.9 mg). Then, the reaction solution was adjusted toabout pH 5 with acetic acid, followed by stirring at room temperaturefor 65 hours. The reaction solution was added with a saturated aqueoussodium bicarbonate solution and then extracted with chloroform. Theorganic layer was washed with saturated saline solution and then driedwith anhydrous sodium sulfate. Subsequently, the solvent was distilledoff. The resulting crude product was purified through silica gel columnchromatography (chloroform/methanol) and treated with hydrochloric acid,thereby obtaining hydrochloride (95.8 mg) of the subject compound as awhite solid.

MS(FAB, Pos.): m/z=511[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.87(6H, t, J=7.2 Hz), 1.68–1.79(4H, m),2.85–2.96(4H, m), 3.78–4.06(5H, m), 4.25(2H, d, J=5.3 Hz), 7.59–7.63(6H,m), 7.89(2H, d, J=8.7 Hz), 7.95(2H, d, J=8.5 Hz), 7.98–8.00(1H, m),8.66(1H, d, J=8.1 Hz), 8.79(1H, d, J=5.0 Hz), 9.10(1H, s), 10.48(1H, s),10.65(1H, brs), 14.78(1H, brs).

Production Example 58 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-4-ylmethyl)-amino]-methyl}-benzamide[Compound No. 58] Example 58-1 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-4-ylmethyl)-amino]-methyl}-benzamide[Compound No. 58]

The compound (100 mg) obtained in Example 47-3 was dissolved in methanol(5.0 ml) and added with pyridin-4-aldehyde (manufactured by Tokyo KaseiKogyo Co., Ltd.) (44.8 μl), followed by the addition of sodiumcyanoborohydride (44.9 mg). Then, the reaction solution was adjusted toabout pH 5 with acetic acid, followed by stirring at room temperaturefor 65 hours. The reaction solution was added with a saturated aqueoussodium bicarbonate solution and then extracted with chloroform. Theorganic layer was washed with saturated saline solution and then driedwith anhydrous sodium sulfate. Subsequently, the solvent was distilledoff. The resulting crude product was purified through silica gel columnchromatography (chloroform/methanol) and treated with hydrochloric acid,thereby obtaining hydrochloride (106 mg) of the subject compound as awhite solid.

MS(FAB, Pos.): m/z=511[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.87(6H, t, J=7.4 Hz), 1.68–1.78(4H, m),2.85–2.94(4H, m), 3.81–4.08(5H, m), 4.25(2H, d, J=5.3 Hz), 7.59–7.64(6H,m), 7.89(2H, d, J=8.8 Hz), 7.96(2H, d, J=8.4 Hz), 8.20(2H, d, J=6.6 Hz),8.86(2H, d, J=6.6 Hz), 10.50(1H, s), 10.73(1H, brs), 14.87(1H, brs).

Production Example 59 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(3-ethoxypyridin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 59] Example 59-1 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(3-ethoxypyridin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 59]

The compound (104 mg) obtained in Example 47-3 was dissolved in methanol(5.0 ml) and added with 3-ethoxy-2-pyridine aldehyde (74.7 mg)synthesized by the method described in Marsais, F et al, Synthesis, 235(1982), followed by the addition of sodium cyanoborohydride (46.6 mg).After that, the reaction solution was adjusted to about pH 5 with aceticacid and then stirred at room temperature for 65 hours. The reactionsolution was added with a saturated aqueous sodium bicarbonate solutionand then extracted with chloroform. The organic layer was washed withsaturated saline solution and then dried with anhydrous sodium sulfate.Subsequently, the solvent was distilled off. The resulting crude productwas purified through silica gel column chromatography(chloroform/methanol) and then treated with hydrochloric acid, therebyobtaining hydrochloride (132 mg) of the subject compound as a whitesolid.

MS(FAB, Pos.): m/z=555[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.87(6H, t, J=7.3 Hz), 1.37(3H, t, J=7.0Hz), 1.67–1.79(4H, m), 2.86–2.96(4H, m), 3.42–3.82(2H, m), 4.12–4.20(4H,m), 4.25–4.30(4H, m), 7.65(2H, s), 7.77(1H, brs), 7.86–7.88(4H, m),7.98(1H, brs), 8.40(1H, d, J=5.1 Hz), 10.39(1H, brs), 10.57(1H, brs).

Production Example 60 Synthesis of[4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxy)-butyl]-dipropylamine[Compound No. 60] Example 60-1 Synthesis of4-{N-Boc(N−1-methanesulfonyl-1H-imidazol-2-ylmethyl)amino]methyl}benzylchloride

The compound (257 mg) obtained in Example 35-2 was dissolved indichloromethane (5.0 ml). The solution was added with diisopropylethylamine (423 μl) and then added with methanesulfonylchloride (157 μl)in an ice bath, followed by stirring overnight at room temperature undera nitrogen atmosphere. After completion of the reaction, a saturatedaqueous sodium bicarbonate solution was added to the solution, and thewhole was stirred. The resultant solution was subjected to extractionwith chloroform and washed with a saturated aqueous sodium bicarbonatesolution, a saturated aqueous ammonium chloride solution, and saturatedsaline solution, followed by drying of the organic layer with anhydroussodium sulfate. The solvent was distilled off and the residue was thenpurified through silica gel column chromatography (hexane/acetone),thereby obtaining the compound (302 mg) as a yellow oily substance.

MS(FAB, Pos.): m/z=414[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=1.31(9H, s), 3.59(3H, brs), 4.51(2H, s),4.63(2H, brs), 4.74(2H, s), 7.05(1H, d, J=1.7 Hz), 7.26(2H, d, J=8.1Hz), 7.40(2H, d, J=8.1 Hz), 7.52(1H, d, J=1.7 Hz).

Example 60-2 Synthesis of 4-dipropylamino-1-butanol

In anhydrous methanol (20 ml), 4-amino-1-butanol (manufactured by TokyoKasei Kogyo Co., Ltd.) (1.03 g) was dissolved. Then, the solution wasadded with sodium cyanoborohydride (2.18 g), acetic acid (5.00 ml), andpropionaldehyde (2.08 ml), followed by stirring under a nitrogenatmosphere at room temperature for 1 week. After completion of thereaction, the solvent was distilled off and the residue was thendissolved in chloroform, followed by stirring after the addition of asaturated aqueous sodium bicarbonate solution. The resultant solutionwas subjected to extraction with chloroform. The extract was washed witha saturated aqueous sodium bicarbonate solution and saturated salinesolution, followed by drying of the organic layer with anhydrous sodiumsulfate. The solvent was distilled off, thereby obtaining the subjectcompound (2.54 g) as a colorless liquid.

MS(FAB, Pos.): m/z=174[M+H]⁺

Example 60-3 Synthesis of[4-(4-{[N-Boc(N-1-methanesulfonyl-1H-imidazol-2-ylmethyl)amino]methyl}benzyloxyl)butyl]dipropylamine

The compound (146 mg) obtained in Example 60-1 was dissolved indichloromethane (2.0 ml). The solution was added with potassiumbicarbonate (53.0 mg) and the compound (61.1 mg) obtained in Example60-2, followed by stirring at room temperature for 6 days. Aftercompletion of the reaction, a saturated aqueous ammonium chloridesolution was added to the solution, and the whole stirred. The solutionwas subjected to extraction with chloroform and the extract was thenwashed with saturated saline solution. Then, the organic layer was driedwith anhydrous sodium sulfate. Subsequently, the solvent was distilledoff and the residue was then purified through silica gel columnchromatography (chloroform/methanol), thereby obtaining the subjectcompound (158 mg) as a colorless crystal.

MS(FAB, Pos.): m/z=551[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=1.04(6H, t, J=7.3 Hz) 1.44(9H, s),1.63–1.68(2H, m), 1.86–1.95(4H, m), 2.07–2.12(2H, m), 3.09–3.22(4H, m),3.41(3H, brs), 3.49(2H, m), 3.75(2H, s), 4.65(2H, s), 4.74(2H, s),7.04(1H, d, J=1.7 Hz), 7.31(1H, d, J=1.7 Hz), 7.36(2H, d, J=8.1 Hz),7.45(1H, d, J=8.1 Hz).

Example 60-4 Synthesis of[4-(4-{[N-(1H-imidazol-2-ylmethyl)amino]methyl}benzyloxy)butyl]dipropylamine

The compound (158 mg) obtained in Example 60-3 was dissolved inanhydrous methanol (1.0 ml) and then added with a 1 mol/l hydrogenchloride/diethyl ether solution (5.00 ml), followed by stirring at roomtemperature for 3 hours. After completion of the reaction, the solventwas distilled off. The residue was added with a 1 mol/l sodium hydroxideaqueous solution and washed with chloroform. The aqueous layer wasevaporated to dryness and then subjected to extraction with chloroform,thereby obtaining the subject compound (81.2 mg) as a white crystal.

MS(FAB, Pos.): m/z=373[M+H]⁺

Example 60-5 Synthesis of[4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxy)-butyl]-dipropylamine[Compound No. 60]

The compound (81.2 mg) obtained in Example 60-4 was dissolved inanhydrous methanol (2.0 ml) and then added with sodium cyanoborohydride(27.4 mg), acetic acid (3.00 ml), and 2-imidazole carboxaldehyde (31.4mg), followed by stirring under a nitrogen atmosphere at 60° C. for 4days. After completion of the reaction, the solvent was distilled off.Then, the residue was dissolved in chloroform and added with a saturatedaqueous sodium bicarbonate solution, followed by stirring. The aqueouslayer was washed with chloroform and then evaporated to dryness. Theresidue was purified through silica gel column chromatography(chloroform/methanol) and treated with hydrochloric acid, therebyobtaining hydrochloride (63.0 mg) of the subject compound as a whitesolid.

MS(FAB, Pos.): m/z=453[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.88(6H, t, J=7.2 Hz), 1.42(2H, t, J=6.9Hz), 1.69–1.79(6H, m), 2.89–2.91(4H, m), 2.92–3.00(2H, m), 3.44(2H, t,J=6.1 Hz), 4.16(4H, s), 4.39(2H, s), 4.72(2H, s), 7.27(2H, d, J=8.2 Hz),7.43(2H, d, J=8.2 Hz), 7.50(2H, s), 7.52(2H, s).

Production Example 61 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1H-benzimidazol-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 61] Example 61-1 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1H-benzimidazol-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 61]

The compound (99.3 mg) obtained in Example 47-3 was dissolved in DMF(3.0 ml) and added with potassium carbonate (81.8 mg) and2-chloromethylbenzimidazole (manufactured by Aldrich Corporation) (43.4mg), followed by stirring at 60° C. for 17 hours. After completion ofthe reaction, the reaction solvent was distilled off and water was thenadded, followed by separation/extraction with chloroform. The organiclayer was dried with anhydrous sodium sulfate. Subsequently, the solventwas distilled off and the residue was then purified through silica gelcolumn chromatography (chloroform/methanol), thereby obtaining thesubject compound (70.0 mg) as a white solid.

MS(FAB, Pos.): m/z=550[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.82(6H, t, J=7.1 Hz), 1.42(4H, sext., J=7.1Hz), 2.31(4H, t, J=7.1 Hz), 3.47(2H, s), 3.71(2H, s), 3.72(2H, s),3.85(2H, s), 7.26(2H, d, J=8.5 Hz), 7.44–7.62(4H, m), 7.60(2H, d, J=8.3Hz), 7.68(2H, d, J=8.5 Hz), 7.91(2H, d, J=8.3 Hz).

Production Example 62 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(2-methylthiazol-4-ylmethyl)-amino]-methyl}-benzamide[Compound No. 62] Example 62-1 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(2-methylthiazol-4-ylmethyl)-amino]-methyl}-benzamide[Compound No. 62]

The compound (99.3 mg) obtained in Example 47-3 was dissolved in DMF(3.0 ml) and then added with potassium carbonate (81.8 mg) and4-chloromethyl-2-methyl thiazole (manufactured by Lancaster SynthesisInc.) (47.9 mg), followed by stirring 60° C. for 17 hours. Aftercompletion of the reaction, the reaction solvent was distilled off andthe residue was then added with water, followed by separation/extractionwith chloroform. The organic layer was dried with anhydrous sodiumsulfate. Then, the solvent was distilled off and the residue was thenpurified through silica gel column chromatography (chloroform/ethylacetate), thereby obtaining hydrochloride (31.2 mg) of the subjectcompound as a white solid.

MS(FAB, Pos.): m/z=531[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.87(6H, t, J=7.3 Hz), 1.62–1.81(4H, m),2.68(3H, s), 2.91(4H, br), 3.82(2H, s), 4.10(2H, s), 4.26 (4H, s),7.52–7.70(7H, m), 7.88(2H, d, J=8.5 Hz), 7.95(2H, d, J=8.1 Hz).

Production Example 63 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(isoquinolin-1-ylmethyl)-amino]-methyl}-benzamide[Compound No. 63] Example 63-1 Synthesis of isoquinoline-1-aldehyde

Isoquinolin-1-yl-methanol (123.7 mg) was dissolved in chloroform (6.2ml) and then added with manganese dioxide (chemically processed product)(1.24 g), followed by stirring at room temperature for 30 minutes. Thereaction solution was filtrated through Celite and the solvent was thendistilled off. The residue was dried under vacuum, thereby obtaining thesubject compound (103.9 mg) as a brown solid.

¹H-NMR(500 MHz, CDCl₃): δ=7.72–7.80(2H, m), 7.88–7.96(2H, m), 8.77(1H,d, J=5.4 Hz), 9.30–9.36(1H, m), 10.3(1H, s).

Example 63-2 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(isoquinolin-1-ylmethyl)-amino]-methyl}-benzamide[Compound No. 63]

The compound (80 mg) obtained in Example 47-3 was dissolved in methanol(5.0 ml) and added with the compound (59.9 mg) obtained in Example 63-1,followed by the addition of sodium cyanoborohydride (35.9 mg). Then, thereaction solution was adjusted to about pH 5 with acetic acid, followedby stirring at room temperature for 14 hours. The reaction solution wasadded with a saturated aqueous sodium bicarbonate solution and thenextracted with chloroform. The organic layer was washed with saturatedsaline solution and then dried with anhydrous sodium sulfate.Subsequently, the solvent was distilled off. The resulting crude productwas purified through silica gel column chromatography(chloroform/methanol) and treated with hydrochloric acid, therebyobtaining hydrochloride (97.1 mg) of the subject compound as a whitesolid.

MS(FAB, Pos.): m/z=561[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.87(6H, t, J=7.4 Hz), 1.67–1.78(4H, m),2.86–2.93(4H, m), 3.92(2H, s), 4.25–4.26(2H, m), 4.36(2H, s), 4.78(2H,brs), 7.57–7.65(6H, m), 7.81–7.86(4H, m), 7.95(1H, brs), 8.11(1H, brs),8.23(1H, brs), 8.48–8.52(1H, m), 8.62(1H, d, J=6.2 Hz), 10.34(1H, s),10.48(1H, brs).

Production Example 64 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 64] Example 64-1 Synthesis of4-methoxy-3,5-dimethylpyridine-2-carboxaldehyde

(4-methoxy-3,5-dimethyl-pyridin-2-yl)methanol (Tokyo Kasei Kogyo Co.,Ltd.) (300 mg) was dissolved in chloroform (15 ml) and added withmanganese dioxide (chemically processed product) (3.00 g), followed bystirring for 3 hours. After completion of the reaction, the solution wasfiltrated through Celite and the solvent was then distilled off, therebyobtaining the subject compound (297 mg) as a white solid.

Example 64-2 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 64]

The compound (70.1 mg) obtained in Example 47-3 was dissolved inmethanol (5.0 ml) and added with the compound (55.2 mg) obtained inExample 64-1, followed by the addition of sodium cyanoborohydride (31.5mg). Then, the reaction solution was adjusted to about pH 5 with aceticacid, followed by stirring at room temperature for 21 hours. Thereaction solution was added with a saturated aqueous sodium bicarbonatesolution and then extracted with chloroform. The organic layer waswashed with saturated saline solution and then dried with anhydroussodium sulfate. Subsequently, the solvent was distilled off. Theresulting crude product was purified through silica gel columnchromatography (chloroform/methanol) and treated with hydrochloric acid,thereby obtaining hydrochloride (36.4 mg) of the subject compound as awhite solid.

MS(FAB, Pos.): m/z=569[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.87(6H, t, J=7.3 Hz), 1.69–1.78(4H, m),2.18(3H, s), 2.31(3H, s), 2.86–2.95(4H, m), 3.79(2H, s), 3.96(3H, s),4.13(2H, s), 4.25–4.26(4H, m), 7.57–7.61(4H, m), 7.67(2H, s),7.84–7.87(4H, m), 8.56(1H, s).

Production Example 65 Synthesis of4-({bis[1-(toluene-4-sulfonyl)-1H-imidazol-2-ylmethyl]-amino}-methyl)-N-(4-dipropylaminomethylphenyl)-benzamide[Compound No. 65] Example 65-1 Synthesis of4-({bis[1-(toluene-4-sulfonyl)-1H-imidazol-2-ylmethyl]-amino}-methyl)-N-(4-dipropylaminomethylphenyl)-benzamide[Compound No. 65]

The compound (50.8 mg) obtained in Example 19-3 was dissolved inanhydrous chloroform (2.0 ml). The solution was added with triethylamine(0.049 ml) and then added with p-toluenesulfonyl chloride (manufacturedby Kanto Kagaku) (57.2 mg), followed by stirring at room temperature for16 hours. After completion of the reaction, chloroform (3.0 ml) wasadded to the solution, and the whole was washed with water. The organiclayer was dried with anhydrous magnesium sulfate. Subsequently, thesolvent was distilled off and the residue was then purified throughsilica gel column chromatography (manufactured by Fuji Silysia ChemicalLtd.) (hexane/ethyl acetate), thereby obtaining the subject compound(15.2 mg) as a white solid.

MS(FAB, Pos.): m/z=809[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.82(6H, t, J=7.3 Hz), 1.42(4H, sext., J=7.5Hz), 2.32(4H, t, J=7.3 Hz), 2.37(6H, s) 3.48(2H, s), 4.00(2H, s),4.05(4H, s), 7.04(2H, d, J=8.4 Hz), 7.08(2H, d, J=1.8 Hz), 7.27(2H, d,J=8.5 Hz), 7.35(4H, d, J=8.1 Hz), 7.70–7.77(10H, m), 10.14(1H, s).

Production Example 66 Synthesis of4-{[bis(1-methanesulfonyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide[Compound No. 66] Example 66-1 Synthesis of4-{[bis(1-methanesulfonyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide[Compound No. 66]

The compound (52.9 mg) obtained in Example 19-3 was dissolved inanhydrous chloroform (2.0 ml). The solution was added with triethylamine(0.054 ml) and then added with methanesulfonyl chloride (manufactured byKanto Kagaku) (0.027 ml), followed by stirring at room temperature for17 hours. After completion of the reaction, chloroform (3.0 ml) wasadded to the solution, and the whole was washed with water. The organiclayer was dried with anhydrous magnesium sulfate. Subsequently, thesolvent was distilled off and the residue was then purified throughsilica gel column chromatography (manufactured by Fuji Silysia ChemicalLtd.) (hexane/ethyl acetate), thereby obtaining the subject compound(31.7 mg) as a white solid.

MS(FAB, Pos.): m/z=656[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.82(6H, t, J=7.3 Hz), 1.42(4H, sext., J=7.2Hz), 2.32(4H, t, J=7.0 Hz), 3.47(2H, s), 3.66(6H, s), 4.01(2H, s),4.04(4H, s), 7.03(2H, d, J=1.8 Hz), 7.26(2H, d, J=8.4 Hz), 7.41(2H, d,J=8.2 Hz), 7.52(2H, d, J=1.7 Hz), 7.69(2H, d, J=8.5 Hz), 7.89(2H, d,J=8.3 Hz), 10.17(1H, s).

Production Example 67 Synthesis of2-({[4-(4-dipropylaminomethylphenylcarbamoyl)-benzyl]-(1-methyl-1H-imidazol-2-ylmethyl)-amino}-methyl)-imidazol-1-carboxylicacid ethyl ester [Compound No. 67] Example 67-1 Synthesis of2-({[4-(4-dipropylaminomethylphenylcarbamoyl)-benzyl]-(1-methyl-1H-imidazol-2-ylmethyl)-amino}-methyl)-imidazol-1-carboxylicacid ethyl ester [Compound No. 67]

The compound (66.2 mg) obtained in Example 49-1 was dissolved inanhydrous chloroform (2.7 ml). Then, the solution was added withtriethylamine (0.028 ml) and then added with methyl chloroformate(manufactured by Kanto Kagaku) (0.015 ml), followed by stirring at roomtemperature for 6 hours. After completion of the reaction, the solutionwas added with chloroform (3.0 ml), followed by washing with water and asaturated aqueous sodium bicarbonate solution. The organic layer wasdried with anhydrous magnesium sulfate and the solvent was thendistilled off, thereby obtaining the subject compound (65.2 mg) as ayellow viscous solid.

MS(FAB, Pos.): m/z=586[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.82(6H, t, J=7.3 Hz), 1.30(3H, t, J=7.2Hz), 1.42(4H, sext., J=7.5 Hz), 2.32(4H, t, J=7.3 Hz), 3.47(2H, s),3.54(3H, s), 3.79(4H, d, J=6.7 Hz), 3.99(2H, s), 4.33(2H, q, J=7.2 Hz),6.76(1H, d, J=1.1 Hz), 6.99(1H, d, J=1.7 Hz), 7.05(1H, d, J=1.1 Hz),7.25(2H, d, J=8.5 Hz), 7.40(2H, d, J=8.2 Hz), 7.54(1H, d, J=1.7 Hz),7.69(2H, d, J=8.4 Hz), 7.87(2H, d, J=8.2 Hz), 10.14(1H, s).

Production Example 68 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-N-methylbenzamide[Compound No. 68] Example 68-1 Synthesis ofN-(4-dipropylaminomethylphenyl)-methylamine

Acetic anhydride (manufactured by Kanto Kagaku) (1.23 ml) was cooledwith ice and then added with formic acid (manufactured by Kanto Kagaku)(0.604 ml), followed by stirring at 50° C. for 2 hours. After thesolution had been stood to cool, anhydrous THF (1.0 ml) was added to thesolution, and the whole was stirred at 0° C. Then, the solution wasadded with a THF solution (2.0 ml) in which the compound (1.075 g)obtained in Example 19-2 was dissolved, followed by stirring for 15minutes. After completion of the reaction, the solvent was distilledoff.

Lithium aluminum hydride (manufactured by Wako Pure Chemical Industries,Ltd.) (493 mg) and anhydrous THF (10 ml) were stirred under ice-cooling.Then, the mixture was added with a solution (24 ml) of the previouslyprepared compound in THF and subjected to thermal reflux for 4 hours.The reaction was terminated with sodium sulfate decahydrate. Theresulting solution was added with a 20% sodium hydroxide aqueoussolution (2.0 ml) and then filtrated through Celite, followed bydistilling the solvent off. The residue was added with chloroform (50ml) and washed with saturated saline solution, followed by drying withanhydrous magnesium sulfate. The solvent was distilled off and theresidue was then purified through silica gel column chromatography(manufactured by Fuji Silysia Chemical Ltd.) (hexane/ethyl acetate),thereby obtaining the subject compound (131.2 mg) as a yellow oilysubstance.

MS(FAB, Pos.): m/z=221[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.87(6H, t, J=7.3 Hz), 1.45–1.52(4H, m),2.35–2.38(4H, m), 2.85(3H, s), 3.48(2H, s), 6.59(2H, d, J=8.3 Hz),7.15(2H, d, J=8.3 Hz).

Example 68-2 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-N-methylbenzamide[Compound No. 68]

The compound (278 mg) obtained in Example 2-2, HOBt (95.9 mg), and DCC(147 mg) were dissolved in anhydrous DMF (11.0 ml), followed by stirringat room temperature for 19 hours. Then, the solution was added with asolution (1.2 ml) of the compound (128 mg) obtained in Example 68-1 inDMF and stirred at room temperature for 20 hours. After completion ofthe reaction, the solvent was distilled off under reduced pressure. Theresidue was dissolved in chloroform and added with 1 mol/l hydrochloricacid to separate the solution into layers. The aqueous layer was addedwith a 1 mol/l sodium hydroxide aqueous solution to adjust the solutionto pH 11. The aqueous layer was extracted with chloroform and theorganic layer was then dried with anhydrous magnesium sulfate. Afterhaving been treated with hydrochloric acid, the product was purifiedthrough silica gel column chromatography (chloroform/methanol/water),thereby obtaining hydrochloride (10.2 mg) of the subject compound as awhite solid.

MS(FAB, Pos.): m/z=514[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.78(6H, t, J=7.3 Hz), 1.63(4H, m), 2.83(4H,m), 3.36(3H, s), 4.06(4H, s), 4.22(2H, s), 7.14(2H, d, J=8.1 Hz),7.22(2H, d, J=8.3 Hz), 7.26(2H, d, J=8.3 Hz), 7.51(2H, d, J=8.3 Hz),7.59(4H, s).

Production Example 69 Synthesis ofN,N-bis(1H-imidazol-2-ylmethyl)-N′,N′-dipropylnonane-1,9-diamine[Compound No. 69] Example 69-1 Synthesis of (9-aminononyl)carbamic acidt-butyl ester

Nonan-1,9-diamine (230 mg) was dissolved in chloroform (5.0 ml) and DMF(10 ml) and then added with di-t-butoxydicarbonate (317 mg). Afterhaving been stirred at room temperature for 30 minutes, the solution wasconcentrated and then purified through silica gel column chromatography(chloroform/methanol), thereby obtaining the subject compound (70.0 mg)as a colorless viscous liquid.

MS(FAB, Pos.): m/z=259[M+H]⁺

Example 69-2 Synthesis of (9-dipropyl)aminononylcarbamic acid t-butylester

The compound (299 mg) obtained in Example 69-1 was dissolved inanhydrous methanol (7.0 ml) and then added with trimethyl orthoformate(0.633 ml). Then, the solution was gradually added with sodiumborohydride (145 mg) under ice-cooling. Subsequently, the mixture washeated back to room temperature and then stirred for 1 hour. Aftercompletion of the reaction, methanol was distilled off and the organiclayer was then extracted with the addition of water and chloroform. Theextract was dried with anhydrous sodium sulfate. The solvent wasdistilled off and the residue was then purified through silica gelcolumn chromatography (chloroform/methanol/water), thereby obtaining thesubject compound (122 mg) as a pale-yellow viscous liquid.

MS(FAB, Pos.): m/z=343[M+H]⁺

Example 69-3 Synthesis of N,N-dipropylnonan-1,9-diamine

The compound (122 mg) obtained in Example 69-2 was dissolved in methanol(1.0 ml) and then added with a 1 mol/l hydrogen chloride/diethyl ethersolution (2.0 ml), followed by stirring at room temperature for 2 hours.The solution was concentrated and dried and then purified through columnchromatography (chloroform/methanol), thereby obtaining hydrochloride(6.0 mg) of the subject compound as a white solid.

MS(FAB, Pos.): m/z=243[M+H]⁺

Example 69-4 Synthesis ofN,N-bis(1H-imidazol-2-ylmethyl)-N′,N′-dipropylnonane-1,9-diamine[Compound No. 69]

The compound (6.0 mg) obtained in Example 69-3 was dissolved inanhydrous methanol (2.0 ml) and added with 2-imidazole carboxaldehyde(6.00 mg), followed by gradual addition of sodium borohydride (3.00 mg)under ice-cooling. The solution was heated back to room temperature andthen stirred for 1 hour. After completion of the reaction, methanol wasdistilled off and the organic layer was extracted with the addition ofwater and chloroform. The extract was dried with anhydrous sodiumsulfate. The solvent was distilled off and the residue was then purifiedthrough silica gel column chromatography (chloroform/methanol/water),followed by washing with ethyl acetate. Consequently, hydrochloride(5.80 mg) of the subject compound was obtained as a pale-yellow viscousliquid.

MS(FAB, Pos.): m/z=403[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.90(6H, t, J=7.3 Hz), 1.12–1.37(12H, m),1.60–1.68(6H, m), 2.36–2.40(2H, m), 2.94–3.02(6H, m), 4.12(4H, s),7.67(4H, s).

Production Example 70 Synthesis ofN-(4-dipropylaminomethylphenyl)-{[(1H-imidazol-2-ylmethyl)-(quinolin-3-ylmethyl)-amino]-methyl}-benzamide[Compound No. 70] Example 70-1 Synthesis ofN-(4-dipropylaminomethylphenyl)-{[(1H-imidazol-2-ylmethyl)-(quinolin-3-ylmethyl)-amino]-methyl}-benzamide[Compound No. 70]

Under ice-cooling, the compound (80.0 mg) obtained in Example 47-3 and3-quinoline carboxaldehyde (Aldrich Corporation) (43.3 mg) weredissolved by the addition of anhydrous methanol (4.0 ml). Subsequently,sodium cyanoborohydride (26.4 mg) and then acetic acid (1.0 ml) wereadded to adjust the solution to pH 5, followed by stirring for 5minutes. The solution was taken out of the ice bath and stirred at roomtemperature for 16 hours. After completion of the reaction, methanol wasdistilled off and the solution was then adjusted to pH 11 to 12 with theaddition of a 1 mol/l sodium hydroxide aqueous solution, followed byextraction with chloroform. The organic layer was washed with saturatedsaline solution and then dried with anhydrous magnesium sulfate. Afterthat, the solvent was distilled off and the residue was then purifiedthrough silica gel column chromatography (manufactured by Fuji SilysiaChemical Ltd.) (chloroform/ethyl acetate). The purified product wastreated with hydrochloric acid, thereby obtaining hydrochloride (20.7mg) of the subject compound as a white crystal.

MS(FAB, Pos.): m/z=561[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.88(6H, t, J=7.3 Hz), 1.62–1.76(4H, m),2.92–2.99(4H, m), 3.82(2H, s), 3.95(2H, s), 4.06(2H, s), 4.28(2H, s),7.52(2H, d, J=8.5 Hz), 7.62(2H, d, J=8.5 Hz), 7.78–8.00(6H, m), 8.15(2H,d, J=8.5 Hz), 8.75(1H, s), 9.17(1H, s).

Production Example 71 Synthesis ofN-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-4-dipropylaminomethylbenzamide[Compound No. 71] Example 71-1 Synthesis of 4-Boc-aminomethylaniline

In dichloromethane (40 ml), 4-aminobenzylamine (manufactured by TokyoKasei Kogyo Co., Ltd.) was dissolved. Then, the solution was added withtriethylamine (2.9 ml) and cooled to 0° C. To the solution, a solutionof di-t-butyl dicarbonate (3.98 g) in dichloromethane (2.0 ml) was addeddropwisely and then the whole was stirred at room temperature for 3hours. After completion of the reaction, the solvent was distilled offunder reduced pressure. The residue was dissolved in chloroform and thenwashed with a 1 mol/l sodium hydroxide aqueous solution and saturatedsaline solution, followed by drying with anhydrous sodium sulfate. Afterfiltration, the solvent was distilled off under reduced pressure and theresidue was then dried under vacuum, thereby obtaining the subjectcompound (3.90 g) as a yellow solid.

MS(FAB, Pos.): m/z=223[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=1.45(9H, s), 3.65(2H, s), 4.19(2H, d, J=5.6Hz), 4.74(1H, brs), 6.64(2H, d, J=8.5 Hz), 7.07(2H, d, J=8.1 Hz).

Example 71-2 Synthesis of4-(N-Boc-aminomethylphenyl)-4-dipropylaminomethylbenzamide

In methanol (4.5 ml), 4-aminomethylbenzoic acid (manufactured by TokyoKasei Kogyo Co., Ltd.) (300 mg) was dissolved. Then, trimethylorthoformate (300 μl) and sodium cyanoborohydride (501 mg) were added tothe solution, and then the whole was cooled to 0° C. Subsequently, thesolution was added with propionaldehyde (357 ml) and then stirred atroom temperature for 6 hours. After completion of the reaction, thesolvent was distilled off under reduced pressure. The residue wasdissolved in chloroform and then washed with a 1 mol/l sodium hydroxideaqueous solution. After that, chloroform was added. The aqueous layerwas neutralized with 1 mol/l hydrochloric acid and extraction withchloroform was then carried out. The solvent was distilled off underreduced pressure and the residue was then dried under vacuum, therebyobtaining a crude product (193.3 mg) as a white viscous solid.Subsequently, the crude product was dissolved in DMF (3.0 ml) and thenadded with WSCI hydrochloride (236 mg) and HOBt (167 mg), followed bystirring at room temperature for 30 minutes. After that, the solutionwas added with the compound (183 mg) obtained in Example 71-1 and thenstirred overnight at room temperature. After completion of the reaction,the solvent was distilled off under reduced pressure. The residue wasdissolved in chloroform and then washed with water, a 1 mol/l sodiumhydroxide aqueous solution, and saturated saline solution, followed bydrying with anhydrous sodium sulfate. After filtration, the solvent wasdistilled off under reduced pressure and the residue was then purifiedthrough silica gel column chromatography (chloroform/methanol), therebyobtaining the subject compound (213 mg) as a pale-yellow viscous liquid.

MS(FAB, Pos.) m/z=440[M+H]⁺

Example 71-3 Synthesis ofN-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-4-dipropylaminomethylbenzamide[Compound No. 71]

The compound (213 mg) obtained in Example 71-2 was dissolved in methanol(1.1 ml) and then added with a 4 mol/l hydrogen chloride/dioxanesolution (1.1 ml), followed by stirring at room temperature for 1.5hours. After completion of the reaction, the solvent was distilled offunder reduced pressure. Then, the residue was then dissolved inchloroform and then washed with a 1 mol/l sodium hydroxide aqueoussolution, followed by extraction with chloroform. After that, theextract was washed with saturated saline solution and then dried withanhydrous sodium sulfate. After filtration, the solvent was distilledoff under reduced pressure and the residue was then dried under vacuum,thereby obtaining a crude product (145 mg) as a white solid. The whitesolid was dissolved in methanol (2.2 ml) and then added with 2-imidazolecarboxaldehyde (123 mg) and acetic acid (145 μl), followed by cooling to0° C. Subsequently, the solution was added with sodium cyanoborohydride(82.5 mg) and stirred overnight at room temperature. After completion ofthe reaction, the solvent was distilled off under reduced pressure. Theresidue was dissolved in chloroform and then washed with a 1 mol/lsodium hydroxide aqueous solution and saturated saline solution,followed by drying with anhydrous sodium sulfate. After filtration, thesolvent was distilled off under reduced pressure. Then, the residue waspurified through silica gel column chromatography (chloroform/ethylacetate) and treated with hydrochloric acid, thereby obtaininghydrochloride (19.0 mg) of the subject compound as a white solid.

MS(FAB, Pos.) m/z=500[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.87(6H, t, J=7.3 Hz), 1.62–1.78(4H, m),2.94(4H, br), 3.62(2H, s), 4.12(4H, s), 4.39(2H, d, J=5.2 Hz), 7.49(2H,d, J=8.4 Hz), 7.62(4H, s), 7.72(2H, d, J=8.4 Hz), 7.80(2H, d, J=8.1 Hz),8.02(2H, d, J=8.1 Hz), 10.38(1H, s), 10.79(1H, br).

Production Example 72 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(8-hydroxyquinolin-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 72] Example 72-1 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(8-hydroxyquinolin-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 72]

The compound (103 mg) obtained in Example 47-3 was dissolved in methanol(5.0 ml). Then, the solution was added with 8-hydroxyquinon-2-aldehyde(85.2 mg) and sodium cyanoborohydride (46.4 mg) in this order, and thenadjusted to about pH 5 with acetic acid, followed by stirring at roomtemperature for 18 hours. The reaction solution was added with asaturated aqueous sodium bicarbonate solution and then subjected toextraction with chloroform. The organic layer was washed with saturatedsaline solution and then dried with anhydrous sodium sulfate.Subsequently, the solvent was distilled off. The resulting crude productwas purified through silica gel column chromatography(chloroform/methanol) and treated with hydrochloric acid, therebyobtaining hydrochloride (93.4 mg) of the subject compound as apale-yellow solid.

MS(FAB, Pos.): m/z=577[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.87(6H, t, J=7.2 Hz), 1.68–1.75(4H, m),2.84–2.96(4H, m), 3.97–4.29(9H, m), 7.37(1H, d, J=6.4 Hz), 7.54–7.62(8H,m), 7.87(2H, d, J=8.7 Hz), 7.93(2H, d, J=8.5 Hz), 8.01(1H, brs),8.67(1H, brs), 10.43(1H, s), 10.65(1H, s), 8.56(1H, brs).

Production Example 73 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyrazine-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 73] Example 73-1 Synthesis of 5-methylpyrazine-2-aldehyde

In methanol (15 ml), 5-methylpyrazine-2-carboxylic acid (manufactured byTokyo Kasei Kogyo Co., Ltd.) (1.25 g) was dissolved. Then, the solutionwas added with WSCI hydrochloride (2.59 g) and N,N-dimethylaminopyridine(1.65 g) in this order, followed by stirring at room temperature for 3hours. The reaction solution was added with water and then extractedwith chloroform. The organic layer was washed with saturated salinesolution and then dried with anhydrous sodium sulfate. The solvent wasdistilled off and the resulting crude product was then purified throughsilica gel column chromatography (chloroform/methanol). The purifiedproduct was dissolved in ethanol (15 ml) and THF (8 ml) and added withcalcium chloride (1.11 g). After that, the reaction solution was cooledto 0° C. and then gradually added with sodium borohydride (757 mg),followed by stirring at room temperature for 19 hours. The reactionsolution was added with a 1 mol/l citric acid solution (40 ml), followedby extraction with ethyl acetate. The organic layer was washed withsaturated saline solution and then dried with anhydrous sodium sulfate,followed by distilling the solvent off. The residue was dissolved inchloroform (10 ml) and then added with manganese dioxide (chemicallyprocessed product) (2.2 g), followed by stirring at room temperature for1 hour. After completion of the reaction, the catalyst was filtrated outthrough Celite and the solvent was then distilled off. The crude productobtained was purified through silica gel column chromatography(chloroform/methanol), thereby obtaining the subject compound (35.9 mg)as a colorless oily substance.

Example 73-2 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyrazine-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 73]

The compound (82.2 mg) obtained in Example 47-3 was dissolved inmethanol (5.0 ml) and added with the compound (35.9 mg) obtained inExample 73-1, followed by the addition of sodium cyanoborohydride (36.9mg). Then, the reaction solution was adjusted to about pH 5 with aceticacid, followed by stirring at room temperature for 16 hours. Thereaction solution was added with a saturated aqueous sodium bicarbonatesolution and then extracted with chloroform. The organic layer waswashed with saturated saline solution and then dried with anhydroussodium sulfate. Subsequently, the solvent was distilled off. Theresulting crude product was purified through silica gel columnchromatography (chloroform/methanol) and treated with hydrochloric acid,thereby obtaining hydrochloride (84.0 mg) of the subject compound as apale-yellow solid.

MS(FAB, Pos.): m/z=526[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.87(6H, t, J=7.3 Hz), 1.69–1.78(4H, m),2.47(3H, s), 2.86–2.95(4H, m), 3.82(2H, s), 3.85(2H, s), 4.11(2H, s),4.26(2H, d, J=5.2 Hz), 7.58–7.62(6H, m), 7.88–7.89(2H, d, J=8.7 Hz),7.95–7.96(2H, d, J=8.4 Hz), 8.47(1H, dd, J=0.6, 1.3 Hz), 8.69(1H, d,J=1.4 Hz), 10.47(1H, s), 10.70(1H, brs), 14.51(1H, brs).

Production Example 74 Synthesis ofN-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 74] Example 74-1 Synthesis ofN-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 74]

Under ice-cooling, the compound (120 mg) obtained in Example 1-4 and thecompound (5.4 mg) obtained in Example 56-1 were dissolved in anhydrousmethanol (7.0 ml), and the solution was added with sodiumcyanoborohydride (46.9 mg), and then adjusted to pH 5 by the addition ofacetic acid (2.0 ml), followed by stirring for 5 minutes. After havingbeen taken out from the ice bath, the solution was stirred at roomtemperature for 16 hours. After completion of the reaction, methanol wasdistilled off and then the residue was added with a 1 mol/l sodiumhydroxide aqueous solution to adjust the solution to pH 11–12, followedby extraction with chloroform. The organic layer was washed withsaturated saline solution and dried with anhydrous magnesium sulfate.After that, the solvent was distilled off and the residue was thenpurified through silica gel column chromatography (manufactured by FujiSilysia Chemical Ltd.) (hexane/ethyl acetate). Then, the purifiedproduct was added with methanol and 1 mol/l hydrochloric acid and thendistillated, thereby obtaining hydrochloride (89.7 mg) of the subjectcompound as a white crystal.

MS(FAB, Pos.): m/z=491[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.90(6H, t, J=7.3 Hz), 1.54–1.62(2H, m),1.63–1.69(6H, m), 2.43(3H, s), 2.97–3.00(4H, m), 3.07(3H, t, J=8.3 Hz),3.28(2H, t, J=6.8 Hz), 3.75(2H, s), 4.08(2H, s), 4.13(2H, s), 7.45(2H,d, J=8.1 Hz), 7.58(2H, s), 7.73(2H, d, J=8.1 Hz), 7.91(1H, d, J=8.1 Hz),8.26(1H, d, J=8.5 Hz), 8.65(1H, s).

Production Example 75 Synthesis ofN-(4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyridine-2-ylmethyl)-amino]-methyl}-benzyl)-N′,N′-dipropylbutane-1,4-diamine[Compound No. 75] Example 75-1 Synthesis of(4-dipropylaminobutyl)-(4-{[(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)carbamicacid t-butyl ester

The compound (0.78 g) obtained in Example 25-4 was dissolved in methanol(20 ml) and added with 2-imidazole carboxaldehyde (214.6 mg), followedby stirring at room temperature for 17 hours. After the solvent had beendistilled off, the residue was dried under vacuum and then dissolved inmethanol (15 ml) and then added with sodium borohydride (217.8 mg),followed by stirring at room temperature for 45 minutes. The reactionsolution was added with a saturated aqueous ammonium chloride solution(10 ml) and stirred at room temperature for 15 minutes. Then, thereaction solution was added with saturated saline solution and extractedwith chloroform, followed by drying with anhydrous sodium sulfate. Afterthe solvent had been distilled off, the residue obtained was purifiedthrough silica gel column chromatography (chloroform/ethyl acetate),thereby obtaining the subject compound (1.01 g) as a yellow solid.

MS(FAB, Pos.): m/z=472[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=0.86(6H, t, J=7.3 Hz), 1.26–1.49(17H, m),2.32–2.35(6H, m), 3.12(1H, brs), 3.21(1H, brs), 3.79(2H, brs), 3.92(2H,brs), 4.12(1H, brs), 4.13(1H, brs), 6.99(2H, s), 7.20(2H, brs), 7.25(2H,d, J=7.5 Hz).

Example 75-2 Synthesis of(4-dipropylaminobutyl)-(4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyridin-2-ylmethyl)amino]methyl}benzyl)carbamicacid t-butyl ester

The compound (61.6 mg) obtained in Example 75-1 was dissolved inmethanol (2.0 ml) and then added with the compound (23.8 mg) obtained inExample 56-1, followed by the addition of sodium cyanoborohydride (15.8mg). The reaction solution was added with acetic acid to adjust thesolution to pH 5, followed by stirring at room temperature for 17 hours.The reaction solution was added with a 1 mol/l sodium hydroxide aqueoussolution and extracted with chloroform. After that, the organic layerwas washed with saturated saline solution and dried with anhydroussodium sulfate. After the solvent had been distilled off, the residueobtained was purified through silica gel column chromatography(chloroform/ethyl acetate), thereby obtaining the subject compound (36.7mg) as a yellow solid.

MS(FAB, Pos.): m/z=577[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=0.85(6H, t, J=7.3 Hz), 1.38–1.45(14H, m),1.49(3H, brs), 2.31–2.53(9H, m), 3.11(1H, brs), 3.20(1H, brs), 3.63(2H,s), 3.67(2H, s), 3.75(2H, s), 4.37(1H, brs), 4.41(1H, brs), 7.05(2H,brs), 7.16–7.19(3H, m), 7.30(2H, d, J=7.8 Hz), 7.49(1H, d, J=7.6 Hz),8.46(1H, brs).

Example 75-3 Synthesis ofN-(4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyridine-2-ylmethyl)-amino]-methyl}-benzyl)-N′,N′-dipropylbutane-1,4-diamine[Compound No. 75]

The compound (35.5 mg) obtained in Example 75-2 was dissolved inmethanol (1.0 ml) and then added with a 1 mol/l hydrogenchloride/diethyl ether solution (2 ml), followed by stirring at 40° C.for 1 hour. The solvent was distilled off, thereby obtaininghydrochloride (36.9 mg) of the subject compound as a yellow solid.

MS(FAB, Pos.): m/z=477[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.91(6H, t, J=7.3 Hz), 1.60–1.68(8H, m),2.38(3H, s), 2.92–3.05(8H, m), 3.71(2H, s), 3.91(2H, brs), 4.06(2H, s),4.09(2H, s), 7.45(4H, s), 7.56(2H, s), 7.70(1H, d, J=7.8 Hz), 8.00(1H,d, J=7.8 Hz), 8.53(1H, brs).

Production Example 76 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1-methyl-1H-imidazol-2-ylmethyl)-(5-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 76] Example 76-1 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(5-methylpyridin-2-ylmethyl)amino]methyl}benzamide

The compound (98.9 mg) obtained in Example 47-3 was dissolved inmethanol (3.0 ml) and then added with the compound (35.3 mg) obtained inExample 56-1, followed by stirring at room temperature for 15 hours.Subsequently, the reaction solvent was distilled off and the residue wasthen dried under vacuum. The residue was redissolved in methanol (3.0ml) and then added with sodium borohydride (16.5 mg) while being stirredunder ice-cooling, followed by stirring at room temperature for 1.5hours. After completion of the reaction, the reaction solvent wasdistilled off and the residue was then added with water, followed byseparation/extraction with chloroform. The organic layer was dried withanhydrous sodium sulfate and the solvent was then distilled off.Subsequently, the residue was purified through silica gel columnchromatography (chloroform/ethyl acetate), thereby obtaining the subjectcompound (40.0 mg) as a white solid.

MS(FAB, Pos.): m/z=445[M+H]⁺

Example 76-2 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1-methyl-1H-imidazol-2-ylmethyl)-(5-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 76]

The compound (40.0 mg) obtained in Example 76-1 was dissolved inmethanol (1.2 ml) and then added with 1-methylimidazol-2-aldehyde (11.9mg) and sodium cyanoborohydride (11.3 mg). Then, the solution wasadjusted to pH 5 with acetic acid and then stirred at room temperaturefor 14 hours. After completion of the reaction, a 1 mol/l sodiumhydroxide aqueous solution was added to the reaction solution, followedby separation/extraction with chloroform. The organic layer was driedwith anhydrous sodium sulfate and the solvent was then distilled off.The residue was purified through silica gel column chromatography(chloroform/ethyl acetate) and then treated with hydrochloric acid,thereby obtaining hydrochloride (42.5 mg) of the subject compound as awhite solid.

MS(FAB, Pos.): m/z=539[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.85(6H, t, J=7.3 Hz), 1.59–1.78(4H, m),2.39(3H, s), 2.94(4H, br), 3.80(2H, s), 4.08(4H, s), 4.25 (2H, s),7.44(2H, s), 7.43–7.55(4H, m), 7.80–7.88(5H, m), 8.20(1H, d, J=4.9 Hz),8.60(1H, s).

Production Example 77 Synthesis of4-{[bis(5-methylpyridin-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide[Compound No. 77] Example 77-1 Synthesis of[4-(4-dipropylaminomethylphenylcarbamoyl)benzyl]carbamic acid t-butylester

In chloroform (20 ml) and DMF (8.0 ml),4-(t-butoxycarbonylaminomethyl)benzoic acid (1.95 g) was dissolved.Then, the solution was added with WSCI hydrochloride (1.50 g) and HOBt(1.08 g), followed by stirring at room temperature at 1 hour. Thereaction solution was added with the compound (1.23 g) obtained inExample 19-2 and chloroform (10 ml), followed by stirring at roomtemperature for 15 hours. The solvent was distilled off and the residueobtained was then purified through silica gel column chromatography(chloroform/methanol), thereby obtaining the subject compound (2.86 g)as a yellow oily substance.

MS(FAB, Pos.): m/z=440[M+H]⁺

Example 77-2 Synthesis of4-aminomethyl-N-(4-dipropylaminomethylphenyl)benzamide

The compound (1.38 g) obtained in Example 77-1 was dissolved in methanol(10 ml) and then added with a 4 mol/l hydrogen chloride/dioxane solution(15 ml), followed by stirring at room temperature for 30 minutes. Thereaction solution was concentrated under reduced pressure and added withanion-exchange resin (Amberlite IRA-410) in methanol to adjust thesolution to pH 8. After the resin had been removed through filtration,the solvent was distilled off, thereby obtaining the subject compound(0.79 g) as a yellow solid.

MS(FAB, Pos.): m/z=340[M+H]⁺

Example 77-3 Synthesis of4-{[bis(5-methylpyridin-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide[Compound No. 77]

The compound (105.7 mg) obtained in Example 77-2 was dissolved inmethanol (3.2 ml) and then added with the compound (90.5 mg) obtained inExample 56-1 and sodium cyanoborohydride (58.7 mg). Then, the solutionwas adjusted to pH 5 with acetic acid and then stirred at roomtemperature for 16 hours. After completion of the reaction, the reactionsolvent was distilled off and a 1 mol/l sodium hydroxide aqueoussolution was added to the residue, followed by separation/extractionwith chloroform. The organic layer was dried with anhydrous sodiumsulfate and the solvent was then distilled off. The residue was purifiedthrough silica gel column chromatography (chloroform/ethyl acetate) andthen treated with hydrochloric acid, thereby obtaining hydrochloride(36.0 mg) of the subject compound as a white solid.

MS(FAB, Pos.): m/z=550[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.85(6H, t, J=7.3 Hz), 1.56–1.76(4H, m),2.37(6H, s), 2.92(4H, br), 4.00(2H, s), 4.18(4H, s), 4.25 (2H, s),7.49(2H, d, J=8.8 Hz), 7.53(2H, d, J=8.3 Hz), 7.71(2H, d, J=8.1 Hz),7.81(2H, d, J=8.1 Hz), 7.83(2H, d, J=8.3 Hz), 8.05(2H, d, J=8.1 Hz),8.57(2H, s).

Production Example 78 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[N-(1H-imidazol-2-ylmethyl)-(4-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 78] Example 78-1 Synthesis of 4-methylpyridine-2-aldehyde

By the same procedures as those of Example 53-1, except that2,4-lutidine was used as a raw material, 4-methylpyridine-2-aldehyde(40.5 mg) was obtained.

MS(FAB, Pos.): m/z=122[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=2.46(3H, s), 7.35(1H, d, J=4.9 Hz), 7.80(1H,s), 8.65(1H, d, J=4.9 Hz), 10.08(1H, s).

Example 78-2 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[N-(1H-imidazol-2-ylmethyl)-(4-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 78]

The compound (80.2 mg) obtained in Example 47-3 was dissolved inmethanol (2.4 ml) and then added with the compound (34.6 mg) obtained inExample 78-1 and sodium cyanoborohydride (18.0 mg). The solution wasadjusted to about pH 5 with acetic acid and then stirred at roomtemperature for 26 hours. After completion of the reaction, the solventwas distilled off and the residue was then dissolved in chloroform,followed by washing with a 1 mol/l sodium hydroxide aqueous solution andsaturated saline solution and drying with anhydrous sodium sulfate. Thesolvent was distilled off and the residue was then purified throughsilica gel column chromatography (chloroform/methanol), therebyobtaining the subject compound (40.1 mg) as a white solid.

MS(FAB, Pos.): m/z=525[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.82(6H, t, J=7.3 Hz), 1.42(4H, sext., J=7.3Hz), 2.32(4H, t, J=7.3 Hz), 2.34(3H, s), 3.47(2H, s), 3.64(2H, s),3.65(2H, s), 3.66(2H, s), 6.86(1H, s), 7.09–7.11(2H, m), 7.25(2H, d,J=8.5 Hz), 7.48(1H, s), 7.57(2H, d, J=8.5 Hz), 7.69(2H, d, J=8.3 Hz),7.90(2H, d, J=8.3 Hz), 8.35(1H, d, J=4.9 Hz), 10.17(1H, s), 11.96(1H,br).

Production Example 79 Synthesis of{2-[4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxy)-phenyl]-ethyl}-dipropylamine[Compound No. 79] Example 79-1 Synthesis of4-(2-dipropylaminoethyl)phenol

Tyramine (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (591 mg) wasdissolved in anhydrous methanol (12 ml) and then added with sodiumcyanoborohydride (812 mg), acetic acid (5.00 ml), and propionaldehyde(777 μl), followed by stirring at room temperature under a nitrogenatmosphere for 2 days. After completion of the reaction, the solvent wasdistilled off. Then, the residue was dissolved in diethyl ether and thenstirred after the addition of distilled water. The solution wassubjected to extraction with diethyl ether and the extract was thenwashed with distilled water and a saturated aqueous ammonium chloridesolution. The organic layer was dried with anhydrous sodium sulfate andthe solvent was then distilled off, thereby obtaining the subjectcompound (412 mg) as a dark brown liquid.

MS(FAB, Pos.): m/z=222[M+H]⁺

Example 79-2 Synthesis of {2-[4-(4-{[N-Boc(N-1-methanesulfonyl-1H-imidazol-2-ylmethyl)amino]methyl}benzyloxy)phenyl]ethyl}dipropylamine

The compound (260 mg) obtained in Example 60-1 was dissolved in DMF (2.0ml) and then added with potassium carbonate (86.8 mg) and the compound(139 mg) obtained in Example 79-1, followed by stirring under a nitrogenatmosphere at 60° C. for 3 days. After completion of the reaction, thesolvent was distilled off. Then, the residue was dissolved in chloroformand added with a saturated aqueous ammonium chloride solution, followedby stirring. The solution was extracted with chloroform and the extractwas then washed with a saturated aqueous sodium bicarbonate solution andsaturated saline solution. Subsequently, the organic layer was driedwith anhydrous sodium sulfate. The solvent was distilled off and theresidue was then purified through silica gel column chromatography(chloroform/methanol/water), thereby obtaining the subject compound (149mg) as a yellow oily substance.

MS(FAB, Pos.): m/z=599[M+H]⁺

Example 79-3 Synthesis of{2-[4-(4-{[N-(1H-imidazol-2-ylmethyl)amino]methyl}benzyloxy)phenyl]ethyl}dipropylamine

The compound (149 mg) obtained in Example 79-2 was dissolved inanhydrous methanol (1.0 ml) and then added with a 4 mol/l hydrogenchloride/dioxane solution (2.00 ml), followed by stirring at roomtemperature for 6 hours. After completion of the reaction, the solventwas distilled off. Then, the residue was added with a 1 mol/l sodiumhydroxide aqueous solution and then washed with chloroform. The aqueouslayer was evaporated to dryness and extracted with chloroform, therebyobtaining the subject compound (67.0 mg) as a colorless oily substance.

MS(FAB, Pos.): m/z=421[M+H]⁺

Example 79-4 Synthesis of{2-[4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxy)-phenyl]-ethyl}-dipropylamine[Compound No. 79]

The compound (67.0 mg) obtained in Example 79-3 was dissolved inanhydrous methanol (1.5 ml) and then added with sodium cyanoborohydride(20.0 mg), acetic acid (1.50 ml), and 2-imidazole carboxaldehyde (23.0mg), followed by stirring under a nitrogen atmosphere at 60° C. for 2days. After completion of the reaction, the solvent was distilled off.Subsequently, the residue was purified through silica gel columnchromatography (chloroform/methanol) and then treated with hydrochloricacid, thereby obtaining hydrochloride (47.1 mg) of the subject compoundas a white solid.

MS(FAB, Pos.): m/z=501[M+H]⁺

Production Example 80 Synthesis of[4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxymethyl)-benzyl]-dipropylamine[Compound No. 80] Example 80-1 Synthesis of methyl4-dipropylaminomethylbenzoate

In anhydrous methanol (30 ml), 4-aminomethylbenzoic acid methyl esterhydrochloride (1.15 g) was dissolved. Then, the solution was added withsodium cyanoborohydride (1.08 g), acetic acid (5.00 ml), andpropionaldehyde (1.03 ml), followed by stirring under a nitrogenatmosphere at room temperature for 1 week. After completion of thereaction, the solvent was distilled off and the residue was thendissolved in chloroform, followed by the addition of a 1 mol/l sodiumhydroxide aqueous solution to adjust the solution to pH 9. The solutionwas subjected to extraction with chloroform. Then, the extract waswashed with a saturated aqueous sodium bicarbonate solution andsaturated saline solution. The organic layer was dried with anhydroussodium sulfate and the solvent was then distilled off, thereby obtainingthe subject compound (1.49 g) as a colorless liquid.

MS(FAB, Pos.): m/z=250[M+H]⁺

Example 80-2 Synthesis of 4-dipropylaminomethylbenzyl alcohol

The compound (1.47 g) obtained in Example 80-1 was dissolved inanhydrous THF (50 ml). Then, the solution was added with lithiumaluminum hydride (671 mg) in an ice bath, followed by stirring at roomtemperature for 1 hour. After completion of the reaction, the solutionwas added with methanol and then added with an aqueous potassium sodiumtartrate solution, followed by stirring. The solution was extracted withchloroform and the extract was then washed with saturated salinesolution. The organic layer was dried with anhydrous sodium sulfate andthe solvent was then distilled off, thereby obtaining the subjectcompound (1.20 g) as a colorless liquid.

MS(FAB, Pos.): m/z=222[M+H]⁺

Example 80-3 Synthesis of[4-(4-{[N-Boc(N-1-methanesulfonyl-1H-imidazol-2-ylmethyl)amino]methyl}benzyloxymethyl)benzyl]dipropylamine

The compound (225 mg) obtained in Example 60-1 was dissolved in DMF (2.0ml) and then added with potassium carbonate (75.2 mg) and the compound(120 mg) obtained in Example 80-2, followed by stirring under a nitrogenatmosphere at 60° C. for 2 days. In addition, potassium iodide (18.0 mg)was added to the solution, and likewise the whole was stirred overnightat 60° C. under a nitrogen atmosphere. After completion of the reaction,the solvent was distilled off. The residue was dissolved in chloroformand then added with a saturated aqueous ammonium chloride solution,followed by stirring. The solution was extracted with chloroform andwashed with a saturated aqueous sodium bicarbonate solution andsaturated saline solution. Subsequently, the organic layer was driedwith anhydrous sodium sulfate. The solvent was distilled off and theresidue was then purified through silica gel column chromatography(chloroform/methanol), thereby obtaining the subject compound (194 mg)as a colorless oily substance.

MS(FAB, Pos.): m/z=599[M+H]⁺

Example 80-4 Synthesis of[4-(4-{[N-(1H-imidazol-2-ylmethyl)amino]methyl}benzyloxymethyl)benzyl]dipropylamine

The compound (193 mg) obtained in Example 80-3 was dissolved inanhydrous methanol (1.0 ml) and then added with a 1 mol/l sodiumhydroxide aqueous solution (2.00 ml), followed by stirring for 2 hoursat room temperature. Subsequently, a 4 mol/l hydrogen chloride/dioxanesolution (3.00 ml) was added to the solution to adjust the solution topH 2, followed by stirring at room temperature for 1 hour. Aftercompletion of the reaction, the solvent was distilled off and theresidue was dissolved in methanol. Subsequently, the solution was addedwith an anion-exchange resin (Amberlite IRA-410) and left to stand. Theresultant was filtrated and the solvent was then distilled off, therebyobtaining the subject compound (136 mg) as a colorless oily substance.

MS(FAB, Pos.): m/z=421[M+H]⁺

Example 80-5 Synthesis of[4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxymethyl)-benzyl]-dipropylamine[Compound No. 80]

The compound (136 mg) obtained in Example 80-4 was dissolved inanhydrous methanol (3.0 ml) and then added with sodium cyanoborohydride(40.6 mg), acetic acid (1.00 ml), and 2-imidazole carboxaldehyde (46.6mg), followed by stirring under a nitrogen atmosphere at 60° C.overnight. After completion of the reaction, the solvent was distilledoff. Subsequently, the residue was purified through silica gel columnchromatography (chloroform/methanol) and then treated with hydrochloricacid, thereby obtaining hydrochloride (109 mg) of the subject compoundas a white solid.

MS(FAB, Pos.): m/z=501[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.87 (6H, t, J=7.2 Hz), 1.78–1.90(4H,m), 2.89–3.08(4H, m), 4.11(2H, s), 4.15(2H, s), 4.58(4H, s), 4.76(4H,s), 7.41–7.53(8H, m), 7.55(4H, s).

Production Example 81 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-([1,2,3]-thiadiazole-4-ylmethyl)-amino]-methyl}-benzamide[Compound No. 81] Example 81-1 Synthesis of [1,2,3]thiadiazol-4-aldehyde

[1,2,3]thiazol-4-carboxylic acid (manufactured by Avocado Co., Ltd.)(1.19 g) was dissolved in a 10% hydrogen chloride/methanol solution(35.7 ml), following thermal reflux for 14 hours. The reaction solventwas distilled off and the residue was dried under vacuum. The driedproduct was dissolved in ethanol (18.0 ml) and THE (9.0 ml) and thenadded with calcium chloride (1.39 mg) and sodium borohydride (0.945 g),followed by stirring at room temperature for 30 minutes. The reactionsolution was added with a 1 mol/l aqueous citric acid solution, followedby separation/extraction with ethyl acetate. The organic layer waswashed with a saturated aqueous sodium bicarbonate solution andsaturated saline solution in this order, and then dried with anhydroussodium sulfate, and the solvent was distilled off. The residue wasredissolved in chloroform (10.5 ml) and then added with manganesedioxide (chemically processed product) (2.10 g), followed by stirring atroom temperature for 1.5 hours. The reaction solution was filtratedusing Celite. The solvent was distilled off and the residue was thenpurified through silica gel column chromatography (chloroform/ethylacetate), thereby obtaining the subject compound (69.2 mg) as a whitesolid.

¹H-NMR(500 MHz, CDCl₃): δ=9.31(1H, s), 10.6(1H, s).

Example 81-2 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-([1,2,3]-thiadiazole-4-ylmethyl)-amino]-methyl}-benzamide[Compound No. 81]

The compound (77.8 mg) obtained in Example 47-3 was dissolved inmethanol (2.3 ml) and then added with the compound (23.3 mg) obtained inExample 81-1 and sodium cyanoborohydride (23.3 mg). Then, the solutionwas adjusted to pH 5 with acetic acid and then stirred at roomtemperature for 19 hours. After completion of the reaction, a 1 mol/lsodium hydroxide aqueous solution was added to the reaction solution,followed by separation/extraction with chloroform. The organic layer wasdried with anhydrous sodium sulfate and the solvent was then distilledoff. The residue was purified through silica gel column chromatography(chloroform/ethyl acetate) and then treated with hydrochloric acid,thereby obtaining hydrochloride (64.9 mg) of the subject compound as awhite solid.

MS(FAB, Pos.): m/z=518[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.88(6H, t, J=7.3 Hz), 1.60–1.80(4H, m),2.96(4H, br), 3.81(2H, s), 4.08(2H, s), 4.26(2H, s), 4.29 (2H, s),7.53(2H, d, J=8.3 Hz), 7.54(2H, s), 7.59(2H, d, J=8.5 Hz), 7.87 (2H, d,J=8.5 Hz), 7.93(2H, d, J=8.3 Hz), 9.15(1H, s).

Production Example 82 Synthesis of4-{[(1-dimethylsulfamoyl-1H-imidazol-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide[Compound No. 82] and Synthesis of4-{[bis(1-dimethylsulfamoyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide[Compound No. 84] Example 82-1 Synthesis of4-{[(1-dimethylsulfamoyl-1H-imidazol-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide[Compound No. 82] and Synthesis of4-{[bis(1-dimethylsulfamoyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide[Compound No. 84]

The compound (55.7 mg) obtained in Example 19-3 was dissolved inanhydrous chloroform (2.2 ml). The solution was added with triethylamine(0.037 ml) and then dimethylsulfamoyl chloride (manufactured by TokyoKasei Kogyo Co., Ltd.) (0.026 ml), followed by stirring at roomtemperature for 42 hours. After the reaction, the solution was addedwith chloroform (3.0 ml) and then washed with water and a saturatedaqueous sodium bicarbonate solution. The organic layer was dried withanhydrous magnesium sulfate. The solvent was distilled off and theresidue was then purified through silica gel column chromatography(manufactured by Fuji Silysia Chemical Ltd.) (chloroform/ethyl acetate),thereby obtaining4-{[(1-dimethylsulfamoyl-1H-imidazol-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide[Compound No. 82] (14.7 mg) as a white solid.

MS(FAB, Pos.): m/z=607[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.82(6H, t, J=7.3 Hz), 1.42(4H, sext., J=7.3Hz), 2.31(4H, t, J=7.3 Hz), 2.76(6H, s), 3.47(2H, s), 3.85(2H, s),3.91(2H, s), 3.95(2H, s), 6.85(1H, s), 7.10(2H, d, J=1.7 Hz), 7.25(2H,d, J=8.5 Hz), 7.49(2H, d, J=8.5 Hz), 7.56(1H, d, J=1.7 Hz), 7.69(2H, d,J=8.5 Hz), 7.88(2H, d, J=8.3 Hz), 10.15(1H, s), 11.90(1H, brs).

Furthermore, as a white solid,4-{[bis(1-dimethylsulfamoyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide[Compound No. 84] (12.7 mg) was obtained from other fraction.

MS(FAB, Pos.): m/z=714[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.82(6H, t, J=7.3 Hz), 1.42(4H, sext., J=7.3Hz), 2.32(4H, t, J=7.3 Hz), 2.78(12H, s), 3.42(2H, s), 4.14(6H, s),7.06(2H, d, J=1.7 Hz), 7.26(2H, d, J=8.5 Hz), 7.39(2H, d, J=8.3 Hz),7.55(2H, d, J=1.7 Hz), 7.69 (2H, d, J=8.5 Hz), 7.86(2H, d, J=8.3 Hz),10.15(1H, s).

Production Example 83 Synthesis of2-({[4-(4-dipropylaminomethylphenylcarbamoyl)-benzyl]-(1-methyl-1H-imidazol-2-ylmethyl)-amino}-methyl)-imidazol-1-carboxylicacid dimethylamide [Compound No. 83] Example 83-1 Synthesis of2-({[4-(4-dipropylaminomethylphenylcarbamoyl)-benzyl]-(1-methyl-1H-imidazol-2-ylmethyl)-amino}-methyl)-imidazol-1-carboxylicacid dimethylamide [Compound No. 83]

The compound (95.0 mg) obtained in Example 49-1 was dissolved inpyridine (5.0 ml) and added with N,N-dimethylcarbamoyl chloride (20.0mg). After the solution had been stirred at room temperature for 15hours, pyridine was distilled off and the residue was then added with asaturated aqueous sodium bicarbonate solution and extracted withchloroform. The extract was concentrated and purified through columnchromatography (chloroform/methanol), thereby obtaining the subjectcompound (45.4 mg) as a white solid.

MS(FAB, Pos.): m/z=585[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.82(6H, t, J=7.3 Hz), 1.38–1.45(4H, m),2.30–2.38(4H, m), 2.73–2.97(6H, m), 3.33(3H, s), 3.47(4H, m), 3.62(4H,d, J=5.8 Hz), 6.79(1H, d, J=1.2 Hz), 6.97(1H, d, J=1.4 Hz), 7.07(1H, d,J=1.2 Hz), 7.26(2H, d, J=6.8 Hz), 7.41(2H, d, J=8.3 Hz), 7.44(1H, d,J=1.4 Hz), 7.69(2H, d, J=8.5 Hz), 7.90(2H, d, J=8.3 Hz), 10.16(1H, s).

Production Example 84 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyrazine-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 85] Example 84-1 Synthesis of pyrazine-2-carboxaldehyde

Pyrazine-2-carboxylic acid methyl ester (Lancaster Synthesis Inc.) (400mg) was dissolved in anhydrous ethanol (8.0 ml) and anhydrous THF (4.0ml) and then added with sodium borohydride (438 mg) and calcium chloride(646 mg), followed by stirring at room temperature for 68 hours. Thesolution was added with a 1 mol/l aqueous citric acid solution andextracted with ethyl acetate. The organic layer was washed with asaturated sodium bicarbonate solution and dried with anhydrous magnesiumsulfate. Subsequently, the solvent was distilled off and the residue wasthen purified through silica gel column chromatography (chloroform/ethylacetate). The purified product was dissolved in chloroform (10 ml) andadded with manganese dioxide (chemically processed product) (2.00 g),followed by stirring for 4 hours. The solution was filtrated throughCelite and the solvent was then distilled off. The residue was purifiedthrough silica gel column chromatography (chloroform/ethyl acetate),thereby obtaining the subject compound (56.0 mg).

MS(EI, Pos.): m/z=108[M]⁺

¹H-NMR(500 MHz, CDCl₃): δ=8.78(1H, d, J=2.4 Hz), 8.89(1H, d, J=2.4 Hz),9.19(1H, s), 10.17(1H, s).

Example 84-2 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyrazine-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 85]

The compound (99 mg) obtained in Example 47-3 and the compound (51.0 mg)obtained in Example 84-1 were dissolved in anhydrous methanol (5.0 ml).The solution was added with sodium cyanoborohydride (35.6 mg) andfurther added with acetic acid (1.0 ml) to adjust the solution to pH 5,followed by stirring for 5 minutes and then stirring at room temperaturefor 17 hours. After completion of the reaction, methanol was distilledoff and the solution was then added with 1 mol/l sodium hydroxide toadjust the solution to pH 11, followed by extraction with chloroform.The organic layer was washed with saturated saline solution and driedwith anhydrous magnesium sulfate. After that, the solvent was distilledoff. Then, the residue was purified through silica gel columnchromatography (chloroform/methanol) and treated with hydrochloric acid,thereby obtaining hydrochloride (16.8 mg) of the subject compound as awhite solid.

MS(FAB, Pos.): m/z=512[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.82(6H, t, J=7.3 Hz), 1.42(4H, sext.,J=7.3 Hz), 2.32(4H, t, J=7.5 Hz), 3.48(2H, s), 3.71(2H, s), 3.73(2H, s),3.77(2H, s), 6.85(1H, s), 7.11(1H, s), 7.27(2H, d, J=8.5 Hz), 7.56(2H,d, J=8.3 Hz), 7.67(2H, d, J=8.5 Hz), 7.89(2H, d, J=8.3 Hz), 8.51(1H, s),8.55(1H, s), 8.84(1H, s).

Production Example 85 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylisoxazol-3-ylmethyl)-amino]-methyl}-benzamide[Compound No. 86] Example 85-1 Synthesis of5-methylisoxazole-3-carboxaldehyde

In anhydrous THF (40 ml), 5-methylisoxazole-3-carboxylic acid methylester (Avogato Co., Ltd.) (2.00 g) was dissolved. In an ice bath, asolution (20 ml) of lithium aluminum hydride (0.67 g) in anhydrous THFwas dropped in the solution over 15 minutes. After 10 minutes, themixture was taken from the ice bath and then stirred at room temperaturefor 1 hour. After completion of the reaction, the resultant solution wasadded with anhydrous sodium sulfate and then added with a 20% sodiumhydroxide aqueous solution (15 ml). The solution was filtrated throughCelite and the solvent was distilled off. The residue was dissolved inchloroform (85 ml) and added with manganese dioxide (chemicallyprocessed product) (17.0 g), followed by stirring for 4.5 hours. Aftercompletion of the reaction, the solution was filtrated through Celiteand the solvent was then distilled off. The residue was purified throughsilica gel column chromatography (chloroform/ethyl acetate), therebyobtaining the subject compound (164 mg) as a white solid.

MS(EI, Pos.): m/z=111[M]⁺

¹H-NMR(500 MHz, CDCl₃): δ=2.53(3H, s), 6.39(1H, s), 10.12(1H, s).

Example 85-2 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylisoxazol-3-ylmethyl)-amino]-methyl}-benzamide[Compound No. 86]

The compound (110 mg) obtained in Example 47-3 and the compound (58.0mg) obtained in Example 85-1 were dissolved in anhydrous methanol (5.0ml). The solution was added with sodium cyanoborohydride (39.4 mg) andthen added with acetic acid (1.0 ml) to adjust the solution to pH 5,followed by stirring for 5 minute and then stirring at room temperaturefor 17 hours. After completion of the reaction, methanol was distilledoff and a 1 mol/l sodium hydroxide aqueous solution was added to adjustthe solution to pH 11, followed by extraction with chloroform. Theorganic layer was washed with saturated saline solution and dried withanhydrous magnesium sulfate, followed by distilling the solvent off.Subsequently, the residue was purified through silica gel columnchromatography (chloroform/methanol), added with methanol and 1 mol/lhydrochloric acid, and distilled off, thereby obtaining hydrochloride(21.3 mg) of the subject compound as a white crystal.

MS(FAB, Pos.): m/z=515[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.82(6H, t, J=7.3 Hz), 1.43(4H, sext.,J=7.3 Hz), 2.32(4H, t, J=7.5 Hz), 2.40(3H, s), 3.48(2H, s), 3.59(2H, s),3.67(2H, s), 3.70(2H, s), 6.34(1H, s), 6.87(1H, s), 7.12(1H, s),7.27(2H, d, J=8.5 Hz), 7.54(2H, d, J=8.3 Hz), 7.68(2H, J=8.5 Hz),7.89(2H, d, J=8.1 Hz).

Production Example 86 Synthesis of4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzoyl)-(2-dipropylaminoethyl)-piperazine[Compound No. 87] Example 86-1 Synthesis of4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzoyl)-(2-dipropylaminoethyl)-piperazine[Compound No. 87]

The compound (103.8 mg) obtained in Example 2-2 was dissolved in DMF(3.1 ml) and then added with DCC (68.8 mg) and HOBt (45.0 mg), followedby stirring at room temperature for 10 days. The solution was added with1-(2-dipropylaminoethyl)piperazine (71.1 mg) and further stirred at thesame temperature for 4 days. The reaction solvent was distilled off andthe residue was then added with 1 mol/l hydrochloric acid, followed bywashing with chloroform. The aqueous layer was adjusted to pH 12 with a1 mol/l sodium hydroxide aqueous solution and then subjected toseparation/extraction with chloroform. The organic layer was dried withanhydrous sodium sulfate. The solvent was distilled off and the residuewas then purified through silica gel column chromatography(chloroform/methanol) and treated with hydrochloride acid, therebyobtaining hydrochloride (52.5 mg) of the subject compound as a whitesolid.

MS(FAB, Pos.): m/z=506[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.88(6H, t, J=7.3 Hz), 1.60–1.76(4H, m),2.78–3.26(12H, m), 3.48–3.58(4H, m), 3.71(2H, m), 4.14(4H, m),7.24–7.56(8H, m).

Production Example 87 Synthesis ofN-(4-cyclohexylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 88] Example 87-1 Synthesis ofcyclohexyl(4-nitrobenzyl)carbamic acid benzyl ester

Commercially available 4-nitrobenzylamine hydrochloride (1.88 g) wasadded with a 1 mol/l sodium hydroxide aqueous solution (12 ml) and thenthe solution was subjected to extraction with chloroform. The solutionwas dried with anhydrous magnesium sulfate, and the solvent wasdistilled off. The residue was dissolved in anhydrous methanol (45 ml)and then added with cyclohexanone (1.55 ml) and trimethyl orthoformate(3.28 ml), followed by stirring at room temperature for 2.5 hours. Thesolution was cooled with ice and added with sodium borohydride (1.13 g),followed by stirring for 4.5 hours. After completion of the reaction,the solvent was distilled off and the residue was then added with water,followed by extraction with chloroform. The extract was washed withsaturated saline solution and dried with anhydrous magnesium sulfate,followed by distilling the solvent off. The residue was dissolved indioxane (25 ml) and cooled with ice. To this solution, benzyloxycarbonylchloride (1.57 ml) and a 4 mol/l sodium hydroxide aqueous solution (2.8ml) were added, and the whole was stirred at room temperature for 4hours. After completion of the reaction, the solvent was distilled offand the residue was then added with water, followed by extraction withchloroform. The extract was dried with anhydrous magnesium sulfate andthe solvent was then distilled off. Subsequently, the residue waspurified through silica gel column chromatography (hexane/ethylacetate), thereby obtaining the subject compound (2.03 g) as a yellowviscous liquid.

MS(FAB, Pos.): m/z=369[M+H]⁺

Example 87-2 Synthesis of (4-aminobenzyl)cyclohexylcarbamic acid benzylester

The compound (1.24 g) obtained in Example 87-1 was dissolved in methanol(12 ml) and THF (6.2 ml) and added with activated carbon (124 mg) andiron trichloride hexahydrate (12.4 mg), followed by thermal reflux for0.5 hour. After standing to cool, the solution was added with hydrazinemonohydrate (0.89 ml) and then subjected to thermal reflux for 3 hours.After completion of the reaction, the resultant was filtrated throughCelite and the solvent was then distilled off. The residue was dissolvedin chloroform and washed with water. The solution was dried withanhydrous magnesium sulfate. The solvent was distilled off, therebyobtaining the subject compound (1.15 g) as a yellow viscous liquid.

MS(FAB, Pos.): m/z=339[M+H]⁺

Example 87-3 Synthesis of[4-(4-{[Boc-(1H-imidazol-2-ylmethyl)amino]methyl}benzoylamino)benzyl]cyclohexylcarbamicacid benzyl ester

The compound (1.15 g) obtained in Example 87-2 was dissolved inanhydrous chloroform (23 ml) and then added with the compound (1.24 g)obtained in Example 1-1, WSCI hydrochloride (717 mg), and HOBt (505 mg),followed by stirring at room temperature for 4 days. After completion ofthe reaction, the solution was washed with 1 mol/l hydrochloric acid, a1 mol/l sodium hydroxide aqueous solution, and saturated salinesolution. The solution was dried with anhydrous magnesium sulfate, andthe solvent was then distilled off. Then, the residue was purifiedthrough silica gel column chromatography (chloroform/methanol), therebyobtaining the subject compound (1.81 g) as a white solid.

MS(FAB, Pos.): m/z=652[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=1.02(1H, br), 1.21–1.24(2H, m), 1.36(9H, s),1.41–1.43(2H, m), 1.46–1.58(3H, m), 1.67(2H, br), 3.84(1H, br),4.35–4.51(6H, m), 5.08–5.12(2H, br), 6.85(1H, s), 7.05(1H, s), 7.21(3H,m), 7.32–7.39(4H, br), 7.68(2H, d, J=8.6 Hz), 7.91(2H, d, J=8.1 Hz),10.18(1H, brs), 11.96(1H, br).

Example 87-4 Synthesis ofcyclohexyl-[4-(4-{[(1H-imidazol-2-ylmethyl)amino]methyl}benzoylamino)benzyl]carbamicacid benzyl ester

The compound (1.82 g) obtained in Example 87-3 was dissolved in methanol(18 ml) and then added with a 4 mol/l hydrogen chloride/dioxane solution(18 ml), followed by stirring at room temperature for 2 hours. After thereaction, the solvent was distilled off. Then, the residue was adjustedto pH 11 with a 1 mol/l sodium hydroxide aqueous solution and extractedwith chloroform, followed by drying with anhydrous magnesium sulfate.Subsequently, the solvent was distilled off, thereby obtaining thesubject compound (1.48 g) as a white solid.

MS(FAB, Pos.): m/z=552[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=1.00–1.05(1H, br), 1.39–1.46(2H, m),1.52–1.56(3H, br), 1.58–1.67(2H, br), 3.68(2H, s), 3.76(2H, s), 3.84(1H,br), 4.42(2H, s), 5.08–5.17(2H, br), 6.80(1H, br), 7.02(1H, br),7.19–7.21(3H, br), 7.31–7.39(4H, m), 7.49(2H, d, J=8.3 Hz), 7.68(2H, d,J=8.5 Hz), 7.90(2H, d, J=8.3 Hz), 10.17(1H, brs).

Example 87-5 Synthesis ofcyclohexyl-[4-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)amino]methyl}benzylamino)benzyl]carbamicacid benzyl ester

The compound (236 mg) obtained in Example 87-4 and 1-methyl-2-imidazolecarboxaldehyde (46.5 mg) were dissolved in anhydrous methanol (7.1 ml).The solution was added with sodium cyanoborohydride (54.0 mg) and thenadjusted to pH 5 with acetic acid, followed by stirring at roomtemperature for 16 hours. After the reaction, the solvent was distilledoff. A 1 mol/l sodium hydroxide aqueous solution was added to theresidue, and chloroform extraction was then carried out. The extract waswashed with saturated saline solution and then dried with magnesiumsulfate, followed by distilling the solvent off. The residue waspurified through silica gel column chromatography (chloroform/methanol),thereby obtaining the subject compound (212 mg) as a white solid.

MS(FAB, Pos.): m/z=646[M+H]⁺

Example 87-6 Synthesis ofN-(4-cyclohexylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 88]

The compound (212 mg) obtained in Example 87-5 was dissolved in methanol(10 ml). After having been cooled with ice, the solution was added witha suspension of 10% palladium-carbon (105 mg) in ethanol (3.0 ml). Afterhaving been subjected to hydrogen displacement, the mixture was stirredunder a hydrogen atmosphere at room temperature for 3 hours. After thereaction, the solution was filtrated through Celite and the solvent wasthen distilled off. Then, the residue was purified through silica gelcolumn chromatography (chloroform/methanol) and treated withhydrochloric acid, thereby obtaining hydrochloride (43.1 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=512[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=1.12(1H, t, J=12.7 Hz), 1.20(2H, q, J=12.7Hz), 1.35–1.42(2H, m), 1.60(1H, d, J=13.0 Hz), 1.77(2H, d, J=13.1 Hz),2.11(2H, d, J=10.1 Hz), 2.93(1H, br), 3.73(3H, s), 3.81(2H, s), 4.11(4H,s), 4.18 (2H, s), 7.54–7.56(4H, m), 7.59(2H, d, J=8.2 Hz), 7.66(2H, s),7.84(2H, d, J=8.7 Hz), 7.93(2H, d, J=8.2 Hz), 9.14(2H, br), 10.38(1H,s), 14.79–14.86(2H, br).

Production Example 88 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-cyclohexylaminomethylphenyl)-benzamide[Compound No. 89] Example 88-1 Synthesis of[4-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzoylamino)benzyl]cyclohexylcarbamic acid benzyl ester

The compound (242 mg) obtained in Example 87-4 and 2-imidazolecarboxaldehyde (63.4 mg) were dissolved in anhydrous methanol (7.2 ml).Then, the solution was added with sodium cyanoborohydride (96.9 mg) andadjusted to pH 5 with acetic acid, followed by stirring at roomtemperature for 2 days. After the reaction, the solvent was distilledoff. The residue was added with a 1 mol/l sodium hydroxide aqueoussolution and extracted with chloroform. Subsequently, the extract waswashed with saturated saline solution and the residue was then driedwith anhydrous magnesium sulfate, followed by distilling the solventoff. The residue was purified through silica gel column chromatography(chloroform/methanol), thereby obtaining the subject compound (282 mg)as a white solid.

MS(FAB, Pos.): m/z=632[M+H]⁺

Example 88-2 Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-cyclohexylaminomethylphenyl)-benzamide[Compound No. 89]

The compound (282 mg) obtained in Example 88-1 was dissolved in methanol(14 ml). After having been cooled with ice, the solution was added witha suspension of 10% palladium-carbon (140 mg) in ethanol (3.0 ml). Afterhaving been subjected to hydrogen displacement, the mixture was stirredunder a hydrogen atmosphere at room temperature for 3 hours. After thereaction, the reaction solution was filtrated through Celite and thesolvent was then distilled off. Then, the residue was purified throughsilica gel column chromatography (chloroform/methanol/water) and treatedwith hydrochloric acid, thereby obtaining hydrochloride (47.1 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=498[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.12(1H, t, J=12.5 Hz), 1.21(2H, q, J=12.5Hz), 1.34–1.41(2H, m), 1.60(1H, d, J=12.2 Hz), 1.77(2H, d, J=14.0 Hz),2.11(2H, d, J=11.0 Hz), 2.94(1H, br), 3.76(2H, s), 4.14(6H, s), 7.54(2H,d, J=8.7 Hz), 7.61(2H, s), 7.63(4H, s), 7.83(2H, d, J=8.5 Hz), 7.92(2H,d, J=8.4 Hz), 9.06(2H, br), 10.36(1H, brs), 14.70(1H, br).

Production Example 89 Synthesis ofN-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N′,N′-dipropylbutane-1,4-diamine[Compound No. 90] Example 89-1 Synthesis ofN-Boc(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-N′,N′-dipropylbutan-1,4-diamine

The compound (231 mg) obtained in Example 75-1 was dissolved inanhydrous methanol (5.0 ml). The solution was added with sodiumcyanoborohydride (61.6 mg), acetic acid (2.00 ml), and1-methyl-2-imidazole carboxaldehyde (80.9 mg), followed by stirringunder a nitrogen atmosphere at room temperature for 6 days. Aftercompletion of the reaction, the solvent was distilled off and theresidue was then dissolved in chloroform, followed by stirring for awhile after the addition of a saturated aqueous sodium bicarbonatesolution. The solution was subjected to extract with chloroform and theextract was then washed with a saturated aqueous sodium bicarbonatesolution and saturated saline solution. The organic layer was dried withanhydrous sodium sulfate. Subsequently, the solvent was distilled offand the residue was then purified through silica gel columnchromatography (chloroform/methanol/water), thereby obtaining thesubject compound (197 mg) as a colorless oily substance.

MS(FAB, Pos.): m/z=566[M+H]⁺

Example 89-2 Synthesis ofN-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N′,N′-dipropylbutane-1,4-diamine[Compound No. 90]

The compound (197 mg) obtained in Example 89-1 was dissolved in methanol(1.0 ml) and added with a 10% hydrogen chloride/methanol solution (3.0ml), followed by stirring overnight at room temperature. Aftercompletion of the reaction, the solvent was distilled off andhydrochloride (159 mg) of the subject compound was obtained as a whitesolid.

MS(FAB, Pos.): m/z=466[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.87(6H, t, J=7.3 Hz), 1.59–1.67(8H, m),2.87(2H, brs), 2.94–2.97(4H, m), 3.01(2H, brs), 3.66(3H, s), 3.69(2H,s), 4.03(4H, s), 4.13(2H, s), 7.34(2H, d, J=8.2 Hz), 7.39(2H, d, J=8.2Hz), 7.40(1H, d, J=2.0 Hz), 7.41(1H, d, J=2.0 Hz), 7.53(2H, s).

Production Example 90 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1-ethyl-1H-imidazol-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 91] Example 90-1 Synthesis of1-ethyl-1H-imidazole-2-carboxaldehyde

In DMF (15 ml), 2-imidazole carboxaldehyde (500 mg) was dissolved. Then,the solution was added with iodoethane (1.25 ml) and sodium hydride (208mg), followed by stirring at room temperature for 5 days. Aftercompletion of the reaction, the solvent was distilled off and theresidue was then added with chloroform, followed by washing with waterand saturated saline solution. The resultant was dried with anhydroussodium sulfate, and the solvent was then distilled off. The residue waspurified through silica gel column chromatography (chloroform/methanol),thereby obtaining the subject compound (280 mg) as a yellow oilysubstance.

¹H-NMR(500 MHz, DMSO-d₆): δ=1.44(3H, t, J=7.3 Hz), 4.44(2H, q, J=7.3Hz), 7.18(1H, s), 7.29(1H, s), 9.82(1H, s).

Example 90-2 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1-ethyl-1H-imidazol-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 91]

The compound (120 mg) obtained in Example 47-3 was dissolved in methanol(5.0 ml) and then added with the compound (58.0 mg) obtained in Example90-1 and sodium cyanoborohydride (18.0 mg). Then, the solution wasadjusted to pH 5 with acetic acid and then stirred at room temperaturefor 2 days. After completion of the reaction, a 1 mol/l sodium hydroxideaqueous solution was added to the reaction solution, followed byseparation/extraction with chloroform. The organic layer was dried withanhydrous sodium sulfate and the solvent was then distilled off. Theresidue was purified through silica gel column chromatography(chloroform/methanol) and then treated with hydrochloric acid, therebyobtaining hydrochloride (107 mg) of the subject compound as a whitesolid.

MS(FAB, Pos.): m/z=528[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.86(6H, t, J=7.3 Hz), 1.29(3H, d, J=7.3Hz), 1.68–1.78(4H, m), 2.86–2.95(4H, m), 3.79(2H, m), 4.10(2H, q, J=7.3Hz), 4.17(2H, s), 4.19(2H, s), 4.25(2H, d, J=5.1 Hz), 7.57–7.66(8H, m),7.87–7.94(4H, m), 10.43(1H, s), 10.54(1H, brs),

Production Example 91 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-propyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 92] Example 91-1 Synthesis of1-propyl-1H-imidazole-2-carboxaldehyde

In DMF 15 ml, 2-imidazole carboxaldehyde (500 mg) was dissolved. Then,the solution was added with 1-iodopropane (1.52 ml) and sodium hydride(208 mg), followed by stirring at room temperature for 5 days. Aftercompletion of the reaction, the solvent was distilled off and theresidue was then added with chloroform, followed by washing with waterand saturated saline solution. The resultant was dried with anhydroussodium sulfate, and the solvent was distilled off. Then, the residue waspurified through silica gel column chromatography (chloroform/methanol),thereby obtaining the subject compound (600 mg) as a yellow oilysubstance.

¹H-NMR(500 MHz, DMSO-d₆): δ=0.93(3H, t, J=7.3 Hz), 1.78–1.85(2H, tq,J=7.3, 7.3 Hz), 4.36(2H, d, J=7.3 Hz), 7.15(1H, s), 7.28(1H, d, J=0.9Hz), 9.81(1H, d, J=0.9 Hz).

Example 91-2 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-propyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 92]

The compound (120 mg) obtained in Example 47-3 was dissolved in methanol(5.0 ml) and then added with the compound (57.0 mg) obtained in Example91-1 and sodium cyanoborohydride (18.0 mg). Then, the solution wasadjusted to pH 5 with acetic acid and then stirred at room temperaturefor 2 days. After completion of the reaction, a 1 mol/l sodium hydroxideaqueous solution was added to the reaction solution, followed byseparation/extraction with chloroform. The organic layer was dried withanhydrous sodium sulfate and the solvent was then distilled off. Theresidue was purified through silica gel column chromatography(chloroform/methanol) and then treated with hydrochloric acid, therebyobtaining hydrochloride (201 mg) of the subject compound as a whitesolid.

MS(FAB, Pos.): m/z=542[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.81(3H, t, J=7.3 Hz), 0.87(6H, t, J=7.3Hz), 1.63–1.77(6H, m), 2.87–2.93(4H, m), 3.78(2H, s), 4.01(2H, d, J=7.3Hz), 4.15(2H, s), 4.17(2H, s), 4.26(2H, d, J=5.3 Hz), 7.56–7.66(8H, m),7.88(2H, d, J=8.7 Hz), 7.92(2H, d, J=8.4 Hz), 10.30(1H, brs), 10.41(1H,s).

Production Example 92 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-({(1H-imidazol-2-ylmethyl)-[1-(2-methoxymethoxyethyl)-1H-imidazol-2-ylmethyl]-amino}-methyl)-benzamide[Compound No. 93] Example 92-1 Synthesis of1-iodo-2-methoxymethoxyethane

A mixture of 2-iodoethanol (2.98 g) and dimethoxymethane (20 ml) wasprepared and then added with p-toluenesulfonic acid monohydrate (330 mg)and lithium bromide (150 mg), followed by stirring at room temperaturefor 16 hours and then stirring at 40° C. for 30 minutes. Aftercompletion of the reaction, triethylamine (0.4 ml) was added to thesolution, and excess part of dimethoxymethane was distilled off. Then,the residue was added with chloroform and washed with water andsaturated saline solution, followed by drying with anhydrous sodiumsulfate. The solvent was distilled off and the residue was then dried,thereby obtaining the subject compound (3.68 g) as a yellow transparentliquid.

¹H-NMR(500 MHz, DMSO-d₆): δ=3.30(2H, t, J=6.6 Hz), 3.40(3H, s), 3.82(2H,t, J=6.6 Hz), 4.68(2H, s).

Example 92-2 Synthesis of1-(2-methoxymethoxyethyl)-1H-imidazole-2-carboxaldehyde

In DMF (15 ml), 2-imidazole carboxaldehyde (300 mg) was dissolved. Then,the compound (1.01 g) obtained in Example 92-1 and sodium hydride (137mg) were added to the solution, and the whole was stirred at roomtemperature for 5 days. After completion of the reaction, the solventwas distilled off and the residue was then added with chloroform,followed by washing with water and saturated saline solution. Theresultant was dried with anhydrous sodium sulfate, and the solvent wasdistilled off. Subsequently, the residue was purified through silica gelcolumn chromatography (chloroform/methanol), thereby obtaining thesubject compound (457 mg) as a yellow viscous liquid.

¹H-NMR(500 MHz, DMSO-d₆): δ=3.21(3H, s), 3.82(2H, t, J=5.1 Hz), 4.55(2H,s), 4.62(2H, t, J=5.1 Hz), 7.28(1H, d, J=0.9 Hz), 7.28(1H, s), 9.82(1H,d, J=0.9 Hz).

Example 92-3 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-({(1H-imidazol-2-ylmethyl)-[1-(2-methoxymethoxyethyl)-1H-imidazol-2-ylmethyl]-amino}-methyl)-benzamide[Compound No. 93]

The compound (120 mg) obtained in Example 47-3 was dissolved in methanol(5.0 ml). The solution was added with the compound (73.0 mg) obtained inExample 92-2 and sodium cyanoborohydride (18.0 mg) and then adjusted topH 5 with acetic acid, followed by stirring at room temperature for 2days. After completion of the reaction, the reaction solution was addedwith a 1 mol/l sodium hydroxide aqueous solution, followed byseparation/extraction with chloroform. The organic layer was dried withanhydrous sodium sulfate and the solvent was then distilled off. Theresidue was purified through silica gel column chromatography(chloroform/methanol), thereby obtaining the subject compound (121 mg)as a yellow oily substance.

MS(FAB, Pos.): m/z=588[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.82(6H, t, J=7.3 Hz), 1.38–1.46(4H, m),2.30–2.36(4H, m), 3.08(3H, s), 3.47(2H, s), 3.53(2H, s), 3.60–3.65(6H,m), 4.12(2H, t, J=5.3 Hz), 4.44(2H, s), 6.76–6.90(2H, m), 7.12(1H, d,J=1.2 Hz), 7.15(2H, d, J=1.2 Hz), 7.26(2H, d, J=8.5 Hz), 7.51(2H, d,J=8.3 Hz), 7.69(2H, d, J=8.5 Hz), 7.90(2H, d, J=8.3 Hz), 10.16(1H, s).

Production Example 93 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-({[1-(2-hydroxyethyl)-1H-imidazol-2-ylmethyl]-(1H-imidazol-2-ylmethyl)-amino}-methyl)-benzamide[Compound No. 94] Example 93-1 Synthesis ofN-(4-dipropylaminomethylphenyl)-4-({[1-(2-hydroxyethyl)-1H-imidazol-2-ylmethyl]-(1H-imidazol-2-ylmethyl)-amino}-methyl)-benzamide[Compound No. 94]

The compound (60.0 mg) obtained in Example 92-3 was dissolved inmethanol (5.0 ml) and then added with 1 mol/l hydrochloric acid (1.5ml). The solution was concentrated and dried under reduced pressure,thereby obtaining hydrochloride (80.0 mg) of the subject compound as awhite solid.

MS(FAB, Pos.): m/z=544[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.87(6H, t, J=7.3 Hz), 1.65–1.76(4H, m),2.87–2.95(4H, m), 3.64–3.66(2H, m), 3.70–3.72(2H, m), 4.15–4.26(8H, m),7.56–7.68(8H, m), 7.88(2H, d, J=8.7 Hz), 7.92(2H, d, J=8.4 Hz),10.27(1H, brs), 10.41(1H, s).

Production Example 94 Synthesis of4-{[bis(1-hexyloxycarbonyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide[Compound No. 95] Example 94-1 Synthesis of4-{[bis(1-hexyloxycarbonyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide[Compound No. 951

The compound obtained in Example 19-3 was treated with an anion-exchangeresin. The treated product was dissolved in chloroform (4.0 ml) andadded with n-hexyl chloroformate (manufactured by Tokyo Kasei Kogyo Co.,Ltd.) (0.054 ml) and triethylamine (0.060 ml), followed by stirring atroom temperature for 16 hours. After completion of the reaction, thesolvent was distilled off. The residue was added with chloroform, washedwith water and saturated saline solution, and dried with anhydroussodium sulfate, followed by distilling the solvent off. Subsequently,the residue was purified through silica gel column chromatography(chloroform/methanol), thereby obtaining the subject compound (66.6 mg)as a white solid.

MS(FAB, Pos.): m/z=756[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.85(6H, t, J=7.3 Hz), 0.88–0.91(6H, m),1.30–1.50(16H, m), 1.71–1.76(4H, m), 2.34–2.38(4H, m), 3.53(2H, s),4.10(2H, s), 4.29–4.31(8H, m), 6.91(2H, d, J=1.6 Hz), 7.32(2H, d, J=8.5Hz), 7.34(2H, d, J=1.6 Hz), 7.38(2H, d, J=8.2 Hz), 7.55(2H, d, J=8.3Hz), 7.73(2H, d, J=8.2 Hz).

Production Example 95 Synthesis of4-{[bis(1-heptyloxycarbonyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide[Compound No. 96] Example 95-1 Synthesis of4-{[bis(1-heptyloxycarbonyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide[Compound No. 96]

The compound (83.8 mg) obtained in Example 19-3 was dissolved inanhydrous dichloromethane (1.5 ml). The solution was added withtriethylamine (70.1 μl) and then added with n-heptyl chloroformate (74.9μl) in an ice bath, followed by stirring overnight under a nitrogenatmosphere at room temperature. After completion of the reaction, thesolution was added with a saturated aqueous sodium bicarbonate solutionand stirred for a while. Then, the solution was extracted withchloroform and washed with a saturated aqueous sodium bicarbonatesolution and saturated saline solution. The organic layer was dried withanhydrous sodium sulfate. Subsequently, the solvent was distilled offand the residue was then purified through silica gel columnchromatography (chloroform/methanol), thereby obtaining the subjectcompound (111 mg) as a brown solid.

MS(FAB, Pos.): m/z=785[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.82(6H, t, J=7.3 Hz), 0.83(6H, t, J=7.0Hz), 1.22–1.34(16H, m), 1.42(4H, sext., J=7.3 Hz), 1.66(4H, quint.,J=7.0 Hz), 2.32(4H, t, J=7.2 Hz), 3.47(2H, s), 3.98(2H, s), 4.17(4H, s),4.27(4H, t, J=6.6 Hz), 6.95(2H, d, J=1.7 Hz), 7.25(2H, d, J=8.4 Hz),7.30(2H, d, J=8.2 Hz), 7.51(2H, d, J=1.7 Hz), 7.68(2H, d, J=8.4 Hz),7.84(2H, d, J=8.2 Hz), 10.12(1H, s).

Production Example 96 Synthesis of4-{[bis(1-butoxycarbonyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide(Compound No. 97] Example 96-1 Synthesis of4-{[bis(1-butoxycarbonyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide[Compound No. 97]

The compound obtained in Example 19-3 was treated with an anion-exchangeresin and then dissolved in anhydrous chloroform (2.8 ml). Subsequently,the solution was added with triethylamine (0.059 ml) and n-butylchloroformate (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.044 ml),followed by stirring at room temperature for 17.5 hours. Aftercompletion of the reaction, the solution was added with chloroform (3.0ml), washed with water, and dried with anhydrous magnesium sulfate,followed by distilling the solvent off. The residue was purified throughsilica gel column chromatography (chloroform/methanol), therebyobtaining the subject compound (66.9 mg) as a brown viscous substance.

MS(FAB, Pos.): m/z=700[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.82(6H, t, J=7.3 Hz), 0.90(6H, t, J=7.3Hz), 1.33–1.45(8H, m), 1.63–1.69(4H, m), 2.32(4H, br), 3.47(2H, br),4.00(2H, s), 4.18(4H, s), 4.29(4H, t, J=6.6 Hz), 6.94(2H, d, J=1.7 Hz),7.25(2H, d, J=7.9 Hz), 7.31(2H, d, J=8.2 Hz), 7.52(2H, d, J=1.8 Hz),7.68(2H, d, J=8.1 Hz), 7.84(2H, d, J=8.4 Hz) 10.12(1H, brs).

Production Example 97 Synthesis ofN-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N-methyl-N′,N′-dipropylbutane-1,4-diamine[Compound No. 98) Example 97-1 Synthesis ofN-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N-methyl-N′,N′-dipropylbutane-1,4-diamine[Compound No. 98]

The hydrochloride of the compound obtained in Example 89-2 was treatedwith an anion-exchange resin. Then, the treated product was dissolved inanhydrous methanol (1.0 ml) and then added with sodium cyanoborohydride(21.9 mg), acetic acid (1.00 ml), and a 36% formaldehyde aqueoussolution (19.6 μl), followed by stirring overnight under a nitrogenatmosphere at room temperature. After completion of the reaction, thesolvent was distilled off. The residue was then dissolved in chloroformand added with a 1 mol/l sodium hydroxide aqueous solution, followed bystirring for a while. The solution was extracted with chloroform andthen the extract was washed with saturated saline solution.Subsequently, the organic layer was dried with anhydrous sodium sulfate.The solvent was distilled off and the residue was then purified throughsilica gel column chromatography (chloroform/ethyl acetate) and treatedwith hydrochloric acid, thereby obtaining hydrochloride (89.9 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=480[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.92(6H, t, J=7.3 Hz), 1.62–1.72(6H, m),1.79(2H, brs), 2.98–3.02(6H, m), 3.08(2H, t, J=7.9 Hz), 3.75(3H, s),3.79(3H, s), 3.91–4.34(8H, m), 7.40(2H, d, J=8.1 Hz), 7.45(2H, d, J=8.1Hz), 7.46(1H, d, J=2.0 Hz), 7.47(1H, d, J=2.0 Hz), 7.59(2H, s).

Production Example 98 Synthesis of4-{[bis-(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(cyclohexyl-methyl-amino)-butyl]-benzamide[Compound No. 99] Example 98-1 Synthesis of4-(cyclohexylamino-butyl)-carbamic acid t-butyl ester

N-(4-aminobutyl)carbamic acid t-butyl ester (manufactured by Tokyo KaseiKogyo Co., Ltd.) (500 mg) was dissolved in anhydrous methanol (10 ml).The solution was added with cyclohexanone (312.8 mg) and sodiumcyanoborohydride (217 mg) and then adjusted to pH 5 with acetic acid,followed by stirring at room temperature for 3 hours. After thereaction, the solvent was distilled off and the residue was added with a1 mol/l sodium hydroxide aqueous solution, followed by extraction withchloroform. The extract was washed with saturated saline solution. Theextract was dried with magnesium sulfate, and the solvent was distilledoff. Consequently, the subject compound (720.3 mg) was obtained as acolorless oily substance.

MS(FAB, Pos.): m/z=271[M+H]⁺

Example 98-2 Synthesis of N¹-cyclohexyl-N¹-methyl-1,4-butanediamine

Under ice-cooling, the compound (718 mg) obtained in Example 98-1 wasdissolved in anhydrous methanol (15 ml) and a 36% formaldehyde aqueoussolution (0.37 ml) was then added to the solution. Next, the solutionwas added with sodium cyanoborohydride (314 mg). Furthermore, aceticacid was added to the solution to adjust the solution to pH 5, followedby stirring for 5 minutes. After the solution had been stirred at roomtemperature for 16 hours, the solvent was distilled off and the residuewas then added with a 1 mol/l sodium hydroxide aqueous solution,followed by extraction with chloroform. The extract was washed withsaturated saline solution and dried with magnesium sulfate, followed bydistilling the solvent off.

The residue was dissolved in methanol (15 ml) and added with a 4mol/hydrogen chloride/dioxane solution (10 ml), followed by stirringunder ice-cooling for 30 minutes. After the reaction, the solvent wasdistilled off and the residue was added with a 1 mol/l sodium hydroxideaqueous solution, followed by extraction with chloroform. The extractwas washed with saturated saline solution and dried with magnesiumsulfate, followed by distilling the solvent off. Consequently, thesubject compound (475 mg) was obtained as a colorless oily substance.

MS(FAB, Pos.): m/z=185[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=1.04–1.12(1H, m), 1.16–1.27(4H, m),1.41–1.54(4H, m), 1.63–1.84(5H, m), 2.25(3H, s), 2.33–2.39(1H, m),2.44(2H, t, J=7.3 Hz), 2.71(2H, t, J=6.7 Hz).

Example 98-3 Synthesis of4-{[bis-(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(cyclohexyl-methyl-amino)-butyl]-benzamide[Compound No. 99]

The compound (120 mg) obtained in Example 2-2 was dissolved in anhydrousDMF (3.0 ml) and added with WSCI hydrochloride (103.3 mg) and HOBt (72.8mg). Then, the solution was added with a solution of the compound (76.0mg) obtained in Example 98-2 in DMF and stirred for 18 hours. After thereaction, the solvent was distilled off and the residue was then addedwith a 1 mol/l sodium hydroxide aqueous solution, followed by extractionwith chloroform. The extract was washed with saturated saline solutionand dried with magnesium sulfate, followed by distilling the solventoff. Subsequently, the residue was purified through silica gel columnchromatography (chloroform/methanol) and then treated with hydrochloricacid, thereby obtaining hydrochloride (20.4 mg) of the subject compoundas a white solid.

MS(FAB, Pos.): m/z=478[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=1.03–1.10(1H, m), 1.42(2H, q, J=7.5 Hz),1.47–1.55(3H, m), 1.68(4H, s), 2.12(3H, s), 2.28(1H, s), 2.37(2H, t,J=7.0 Hz), 3.25(2H, t, J=7.0 Hz), 3.54(2H, s), 3.59(4H, s), 6.87(2H, s),7.15(2H, s), 7.48–7.50(2H, m), 7.76–7.78(2H, m).

Production Example 99 Synthesis ofN-[4-(cyclohexyl-methyl-amino)-butyl]-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 100] Example 99-1 Synthesis of{4-[4-(cyclohexyl-methylamino)-butylcarbamoyl]-benzyl}-(1H-imidazol-2-ylmethyl)-carbamicacid t-butyl ester

The compound (401.1 mg) obtained in Example 98-2 was dissolved inanhydrous chloroform (12 ml). Then, the solution was added with thecompound (795.3 mg) obtained in Example 1-1, HOBt (324.3 mg), and WSCIhydrochloride (460.1 mg) and stirred at room temperature for 16 hours.After the reaction, the solution was added with water and then subjectedto extraction with chloroform. The extract was washed with a 1 mol/lsodium hydroxide aqueous solution and saturated saline solution anddried with anhydrous magnesium sulfate. The solvent was distilled offand the residue was then purified through silica gel columnchromatography (chloroform/methanol), thereby obtaining the subjectcompound (778.9 mg) as a white solid.

MS(FAB, Pos.): m/z=497[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=1.02–1.04(1H, m), 1.06–1.16(4H, m), 1.34(9H,s), 1.37–1.42(2H, m), 1.48–1.54(3H, m), 1.67–1.70(4H, m), 2.12(3H, s),2.24–2.27(1H, m), 2.37(2H, t, J=6.9 Hz), 3.22–3.26(2H, m), 4.32(1H, br),4.41(2H, br), 4.47(1H, br), 6.84(1H, s), 7.04(1H, s), 7.24(2H, br),7.78(2H, d, J=8.2 Hz), 8.42(1H, t, J=5.5 Hz), 11.95(1H, br).

Example 99-2 Synthesis ofN-[4-(cyclohexyl-methyl-amino)-butyl]-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 100]

The compound (778.9 mg) obtained in Example 99-1 was dissolved inmethanol (7.8 ml) and added with a 4 mol/l hydrogen chloride/dioxanesolution (7.8 ml), followed by stirring at room temperature for 4 hours.After the reaction, the solvent was distilled off. The residue was addedwith a 1 mol/l sodium hydroxide aqueous solution, followed by extractionwith chloroform. The extract was dried with anhydrous magnesium sulfateand the solvent was then distilled off.

The residue was dissolved in anhydrous methanol (28 ml) and added with1-methyl-2-imidazole carboxaldehyde (259.9 mg) and sodiumcyanoborohydride (197.3 mg), followed by adjusting the solution to pH 5with acetic acid and stirring at room temperature for 3 days. After thereaction, the solvent was distilled off. Then, the residue was addedwith a 1 mol/l sodium hydroxide aqueous solution, followed by extractionwith chloroform. The extract was dried with anhydrous magnesium sulfate.The solvent was distilled off. Then, the residue was then purifiedthrough silica gel column chromatography (chloroform/methanol) andtreated with hydrochloric acid, thereby obtaining hydrochloride (802.0mg) of the subject compound as a white solid.

MS(FAB, Pos.): m/z=492[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=1.08–1.10(1H, m), 1.22–1.29(2H, m),1.37–1.42(2H, m), 1.51–1.60(3H, m), 1.68–1.79(4H, m), 2.00(1H, d, J=11.4Hz), 2.09(1H, d, J=11.9 Hz), 2.62(3H, d, J=4.9 Hz), 2.96(1H, m),3.08–3.17(2H, m), 3.27(2H, q, J=6.3 Hz), 3.71(3H, s), 3.76(2H, s),4.20(2H, s), 7.49–7.55(4H, m), 7.64(2H, s), 7.79(2H, d, J=8.2 Hz),8.63(1H, t, J=5.3 Hz), 10.52(1H, br), 15.04(2H, br).

Production Example 100 Synthesis of4-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethyl-phenyl)-benzamide[Compound No. 101] Example 100-1 Synthesis of3,5-dimethyl-pyridine-2-carboxaldehyde

In dichloromethane (15.0 ml), 2,3,5-trimethyl-pyridine (1.29 g) wasdissolved. The reaction solution was cooled to 0° C. and added withmeta-chloroperbenzoic acid (2.53 g), followed by stirring at roomtemperature for 1.5 hours. The reaction solution was added with a 1mol/l sodium hydroxide aqueous solution and then subjected to extractionwith chloroform. Subsequently, the organic layer was washed withsaturated saline solution and dried with anhydrous sodium sulfate. Thedrying agent was filtrated out and the solvent was then distilled off,followed by dissolving the resulting residue in dichloromethane (25.0ml). The reaction solution was added with trifluoroacetic anhydride (2.8ml) and subjected to thermal reflux for 3.5 hours. After the reactionsolution had been cooled to room temperature, the solvent was distilledoff. The residue obtained was dissolved in methanol (60.0 ml). Afterhaving been cooled to 0° C., the reaction solution was added with a12.5% sodium methoxide/methanol solution to adjust to pH 10, followed bystirring at room temperature for 16.5 hours. After the solvent had beendistilled off, the residue was added with distilled water and extractedwith chloroform. The organic layer was washed with saturated salinesolution and dried with anhydrous sodium sulfate. The drying agent wasfiltrated out and the solvent was then distilled off, followed bydissolving the resulting residue in chloroform (30.0 ml). The reactionsolution was added with manganese dioxide (chemically processed product)(6.10 g) and then stirred at room temperature for 18 hours. The reactionsolution was filtrated through Celite. The solvent in the filtrate wasdistilled off and the residue obtained was then purified through silicagel column chromatography (chloroform/ethyl acetate), thereby obtainingthe subject compound (1.14 g) as a yellow oily substance.

MS(FAB, Pos.): m/z=136[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=2.40(3H, s), 2.63(3H, s), 7.43(1H, brs),8.48(1H, brs), 10.16(1H, s).

Example 100-2 Synthesis of4-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethyl-phenyl)-benzamide[Compound No. 101]

The compound (146.2 mg) obtained in Example 47-3 was dissolved inanhydrous methanol (5.8 ml) and added with the compound (71.6 mg)obtained in Example 100-1 and sodium cyanoborohydride (66.0 mg),followed by adjusting the solution to pH 5 with acetic acid and stirringat room temperature for 16.5 hours. After the reaction, the solution wasadded with chloroform and washed with a 1 mol/l sodium hydroxide aqueoussolution. Then, the solution was dried with anhydrous magnesium sulfate.The solvent was distilled off. The residue was purified through silicagel column chromatography (chloroform/methanol) and treated withhydrochloric acid, thereby obtaining hydrochloride (110.7 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=539[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.89(6H, t, J=7.3 Hz), 1.64–1.75(4H, m),2.32(3H, s), 2.37(3H, s), 2.92–2.99(4H, m), 3.81(2H, s), 4.07(2H, s),4.20(2H, s), 4.28(2H, s), 7.51–7.54(4H, m), 7.63(2H, s), 7.85(4H, t,J=8.5 Hz), 8.04(1H, br), 8.47(1H, s).

Production Example 101 Synthesis ofN-(4-dipropylaminomethyl-phenyl)-4-{[(5-ethyl-pyridin-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 102] Example 101-1 Synthesis of5-ethyl-pyridine-2-carboxaldehyde

In dichloromethane (25.0 ml), 5-ethyl-2-methyl-pyridine (2.31 g) wasdissolved. The reaction solution was cooled to 0° C. and added withmeta-chloroperbenzoic acid (4.43 g), followed by stirring at roomtemperature for 2.5 hours. The reaction solution was added with a 1mol/l sodium hydroxide aqueous solution and then subjected to extractionwith chloroform. Subsequently, the organic layer was washed withsaturated saline solution and dried with anhydrous sodium sulfate. Thedrying agent was filtrated out and the solvent was then distilled off,followed by dissolving the resulting residue in dichloromethane (40.0ml). The reaction solution was added with trifluoroacetic anhydride (5.6ml) and subjected to thermal reflux for 3.5 hours. After the reactionsolution had been cooled to room temperature, the solvent was distilledoff. The residue obtained was dissolved in methanol (80.0 ml). Afterhaving been cooled to 0° C., the reaction solution was added with a12.5% sodium methoxide/methanol solution and adjusted to pH 10, followedby stirring at room temperature for 16.5 hours. After the solvent hadbeen distilled off, the residue was added with distilled water andextracted with chloroform. The organic layer was washed with saturatedsaline solution and dried with anhydrous sodium sulfate. The dryingagent was filtrated out and the solvent was then distilled off, followedby dissolving the resulting residue in chloroform (50.0 ml). Thereaction solution was added with manganese dioxide (chemically processedproduct) (7.44 g) and then stirred at room temperature for 18 hours. Thereaction solution was filtrated through Celite. The solvent in thefiltrate was distilled off and the residue obtained was then purifiedthrough silica gel column chromatography (chloroform/ethyl acetate),thereby obtaining the subject compound (515.6 mg) as a yellow oilysubstance.

MS(FAB, Pos.): m/z=136[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=1.31(3H, t, J=7.6 Hz), 2.77(2H, q, J=7.6 Hz),7.70(1H, d, J=7.8 Hz), 7.91(1H, d, J=7.8 Hz), 10.06(1H, s).

Example 101-2 Synthesis ofN-(4-dipropylaminomethyl-phenyl)-4-{[(5-ethyl-pyridin-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide[Compound No. 102]

The compound (147.4 mg) obtained in Example 47-3 was dissolved inanhydrous methanol (5.8 ml) and added with the compound (71.6 mg)obtained in Example 101-1 and sodium cyanoborohydride (66.0 mg),followed by adjusting the solution to pH 5 with acetic acid and stirringat room temperature for 16.5 hours. After the reaction, the solution wasadded with chloroform and washed with a 1 mol/l sodium hydroxide aqueoussolution. Then, the solution was dried with anhydrous magnesium sulfate.The solvent was distilled off. The residue was purified through silicagel column chromatography (chloroform/methanol) and treated withhydrochloric acid, thereby obtaining hydrochloride (65.1 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=539[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.88(6H, t, J=7.5 Hz), 1.19(3H, t, J=7.5Hz), 1.64–1.75(4H, m), 2.71(2H, q, J=7.5 Hz), 2.92–2.98(4H, m), 3.80(2H,s), 4.02(2H, s), 4.14(2H, s), 4.28(2H, s), 7.53(4H, d, J=7.0 Hz),7.60(2H, s), 7.78(1H, d, J=8.6 Hz), 7.85–7.88(4H, m), 8.11(1H, br),8.57(1H, br).

Production Example 102 Synthesis ofN-(4-cyclohexylamino-butyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl]-benzenesulfonamide[Compound No. 103] Example 102-1 Synthesis of{4-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzenesulfonylamino]-butyl}-carbamicacid t-butyl ester

The compound (1.4396 g) obtained in Example 24-2 was dissolved inanhydrous chloroform (28 ml) and then added with triethylamine (0.689ml), followed by ice-cooling. Then, the solution was added with(4-aminobutyl)-carbamic acid t-butyl ester (852.9 mg) and stirred atroom temperature for 2.5 hours. After the reaction, the solution waswashed with water and dried with anhydrous magnesium sulfate. Thesolvent was distilled off and the residue was then purified throughsilica gel column chromatography (chloroform/methanol), therebyobtaining the subject compound (1.4440 g) as a white solid.

MS(FAB, Pos.): m/z=488[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=1.29–1.36(4H, m), 1.35(9H, s), 2.67(2H, d,J=4.9 Hz), 2.82(2H, d, J=6.1 Hz), 4.86(2H, s), 6.58(1H, t, J=5.7 Hz),7.51(2H, d, J=8.5 Hz), 7.57(1H, t, J=6.0 Hz), 7.73(2H, d, J=8.4 Hz),7.86–7.93(4H, m).

Example 102-2 Synthesis of[4-(4-{[(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzenesulfonylamino)-butyl]-carbamicacid t-butyl ester

The compound (1.444 g) obtained in Example 102-1 was dissolved in a 40%methylamine/methanol solution (21.6 ml) and stirred at room temperaturefor 16 hours. After the reaction, the solvent was distilled off and theresidue was then added with chloroform. The solution was added with a 1mol/l sodium hydroxide aqueous solution and subjected to extraction withchloroform. The extract was washed with saturated saline solution anddried with anhydrous magnesium sulfate. The solvent was distilled off.The residue was dissolved in anhydrous methanol (35.5 ml) and then addedwith 2-imidazole carboxaldehyde (357.5 mg) and trimethyl orthoformate(0.814 ml), followed by stirring at room temperature for 2 hours. Thesolution was cooled with ice and then added with sodium borohydride(281.5 mg), followed by stirring at room temperature for 3 hours. Afterthe reaction, the solvent was distilled off and the residue was thenadded with water, followed by extraction with chloroform. The extractwas washed with saturated saline solution and dried with anhydrousmagnesium sulfate. The solvent was distilled off and the residue wasthen purified through silica gel column chromatography(chloroform/methanol), thereby obtaining the subject compound (819.2 mg)as a white solid.

MS(FAB, Pos.): m/z=438[M+H]⁺

Example 102-3 Synthesis of[4-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzenesulfonylamino)-butyl]-carbamicacid t-butyl ester

The compound (817.3 mg) obtained in Example 102-2 was dissolved inanhydrous methanol (24.5 ml) and added with 1-methyl-2-imidazolealdehyde(309.4 mg) and sodium cyanoborohydride (235.0 mg). Then, the solutionwas adjusted to pH 5 with acetic acid and stirred at room temperaturefor 24 hours. After the reaction, the solvent was distilled off. Theresidue was added with a 1 mol/l sodium hydroxide aqueous solution andthen subjected to extraction with chloroform. The extract was dried withanhydrous magnesium sulfate and the solvent was distilled off.Subsequently, the residue was purified through silica gel columnchromatography (chloroform/methanol), thereby obtaining the subjectcompound (910.0 mg) as a white solid.

MS(FAB, Pos.): m/z=532[M+H]⁺

Example 102-4 Synthesis ofN-(4-amino-butyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzenesulfonamide

The compound (902.3 mg) obtained in Example 102-3 was dissolved inmethanol (4.0 ml) and added with a 4 mol/l hydrogen chloride/dioxanesolution (4.0 ml), followed by stirring at room temperature for 8.5hours. After the reaction, the solvent was dissolved off. The residuewas added with a 1 mol/l sodium hydroxide aqueous solution (7 ml) andsubjected to extraction with chloroform. Then, the extract was driedwith magnesium sulfate and the solvent was dissolved off. The residuewas then purified through a solid-phase extraction column (ODS type),thereby obtaining the subject compound (844.3 mg) as a brown viscoussolid.

MS(FAB, Pos.): m/z=432[M+H]⁺

Example 102-5 Synthesis ofN-(4-cyclohexylamino-butyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzenesulfonamide[Compound No. 103]

The compound (173.5 mg) obtained in Example 102-4 was dissolved inanhydrous methanol (7.0 ml). Then, the solution was added withcyclohexanone (0.083 ml) and sodium cyanoborohydride (75.4 mg) andadjusted to pH 5 with acetic acid, followed by stirring at roomtemperature for 16.5 hours. After the reaction, the solvent wasdistilled off. Subsequently, the residue was added with a 1 mol/l sodiumhydroxide aqueous solution (7.0 ml), followed by extraction withchloroform. The extract was dried with magnesium sulfate and the solventwas then distilled off. The residue was purified through silica gelcolumn chromatography (chloroform/methanol) and then treated withhydrochloric acid, thereby obtaining hydrochloride (161.6 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=514[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=1.09–1.11(1H, m), 1.19–1.30(4H, m),1.44–1.47(2H, m), 1.60(3H, d, J=7.9 Hz), 1.76(2H, brs), 1.99(2H, brs),2.69 (t, J=6.4 Hz), 2.86(2H, t, J=7.6 Hz), 2.94(1H, br), 3.73(3H, s),3.81(2H, s), 4.10(2H, s), 4.17(2H, s), 7.46–7.60(4H, m), 7.61(2H, d,J=5.0 Hz), 7.66(2H, d, J=8.4 Hz).

Production Example 103 Synthesis ofN-cyclohexyl-N′-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N′-methyl-butane-1,4-diamine[Compound No. 104] Example 103-1 Synthesis of4-(t-butoxycarbonylaminomethyl)benzoic acid methyl ester

Commercially available 4-aminomethylbenzoic acid methyl ester (16.3 g)was dissolved in chloroform (489 ml) and added with triethylamine (14.6ml) and di-t-butyl dicarbonate (10.6 g), followed by stirring at roomtemperature for 2 hours. The reaction solution was added with water andsubjected to separation/extraction with chloroform. The resultingorganic layer was dried with anhydrous sodium sulfate and thenconcentrated under reduced pressure, thereby obtaining the subjectcompound (24.85 g).

Example 103-2 Synthesis of (4-hydroxymethyl-benzyl)-carbamic acidt-butyl ester

Lithium aluminum hydride (5.21 g) was suspended in THF (243 ml). Then, asolution of the compound (24.3 g) obtained in Example 103-1 in THF (243ml) was gradually added to the suspension over 50 minutes while stirringunder ice-cooling, followed by stirring at room temperature for 1 hour.The reaction solution was added with sodium sulfate decahydrate and a20% sodium hydroxide aqueous solution and then filtrated through Celite.The filtrate was concentrated under reduced pressure and dried undervacuum, thereby obtaining the subject compound (18.5 g).

Example 103-3 Synthesis of (4-formyl-benzyl)-carbamic acid t-butyl ester

The compound (18.0 g) obtained in Example 103-2 was dissolved inchloroform (540 ml) and then added with manganese dioxide (chemicallyprocessed product) (118 g), followed by stirring at room temperature for15 hours. The reaction solution was filtrated through Celite and thefiltrate was then concentrated under reduced pressure. The residue waspurified through silica gel column chromatography (chloroform/ethylacetate), thereby obtaining the subject compound (17.1 g) as a whitesolid.

Example 103-4 Synthesis of14-[4-(t-butoxycarbonylamino-methyl)-benzylamino]-butyl}-carbamic acidbenzyl ester

The compound (951.6 mg) obtained in Example 103-3 was dissolved inanhydrous methanol (38 ml) and added with (4-amino-butyl)-carbamic acidbenzyl ester (898.0 mg) and trimethyl orthoformate (1.33 ml), followedby stirring at room temperature for 15.5 hours. After that, the solutionwas cooled with ice and added with sodium borohydride (458.5 mg),followed by stirring at room temperature for 1.5 hours. After thereaction, the solvent was distilled off and the residue was then addedwith water, followed by extraction with chloroform. The extract waswashed with saturated saline solution and dried with anhydrous magnesiumsulfate. The solvent was distilled off and the residue was then purifiedthrough silica gel column chromatography (chloroform/ethyl acetate),thereby obtaining the subject compound (1.1479 g) as a colorless oilysubstance.

MS(FAB, Pos.): m/z=442[M+H]⁺

Example 103-5 Synthesis of{4-[(4-{[(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-methyl-amino]-butyl}-carbamicacid benzyl ester

The compound (1.1479 g) obtained in Example 103-4 was dissolved inanhydrous methanol (33 ml) and added with a 36% formaldehyde aqueoussolution (0.602 ml) and sodium cyanoborohydride (490.1 mg). Then, thesolution was adjusted to pH 5 with acetic acid and stirred at roomtemperature for 20 hours. After the reaction, the solution was addedwith chloroform and washed with a 1 mol/l sodium hydroxide aqueoussolution, followed by drying with anhydrous magnesium sulfate. Then, thesolvent was distilled off.

The residue was dissolved in methanol (12 ml) and then added with a 4mol/l hydrogen chloride/dioxane solution (12 ml), followed by stirringat room temperature for 4 hours. After the reaction, the solvent wasdistilled off. The residue was added with a 1 mol/l sodium hydroxideaqueous solution and extracted with chloroform. The extract was driedwith anhydrous magnesium sulfate and the solvent was then distilled off.

The residue was dissolved in anhydrous methanol (33 ml) and added with2-imidazole carboxaldehyde (339.2 mg) and trimethyl orthoformate (0.771ml), followed by stirring at room temperature for 14 hours.Subsequently, the solution was cooled with ice and then added withsodium borohydride (266.7 mg), followed by stirring at room temperaturefor 8 hours. After the reaction, the solvent was distilled off. Theresidue was added with water and subjected to extraction withchloroform. The extract was washed with saturated saline solution anddried with anhydrous magnesium sulfate. The solvent was distilled offand the residue was then purified through silica gel columnchromatography (chloroform/methanol), thereby obtaining the subjectcompound (608.7 mg) in a colorless oily substance.

MS(FAB, Pos.): m/z=435[M+H]⁺

Example 103-6 Synthesis of{4-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-methyl-amino]-butyl}-carbamicacid benzyl ester

The compound (608.7 mg) obtained in Example 103-5 was dissolved inanhydrous methanol (24 ml) and added with 1-methyl-2-imidazolecarboxaldehyde (231.3 mg) and sodium cyanoborohydride (176.0 mg). Thesolution was adjusted to pH 5 with acetic acid, followed by stirring atroom temperature for 3 days. After the reaction, the solvent wasdistilled off. The residue was added with a 1 mol/l sodium hydroxideaqueous solution and subjected to extraction with chloroform. Theextract was dried with anhydrous magnesium sulfate. The solvent wasdistilled off and the residue was then purified through silica gelcolumn chromatography (chloroform/methanol), thereby obtaining thesubject compound (502.6 mg) as a colorless oily substance.

MS(FAB, Pos.): m/z=530[M+H]⁺

Example 103-7 Synthesis ofN¹-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N¹-methyl-butan-1,4-diamine

The compound (502.6 mg) obtained in Example 103-6 was dissolved inmethanol (2.5 ml) and cooled with ice. Then, the solution was added witha suspension of 10% palladium-carbon (251.3 mg) in ethanol (2 ml),followed by stirring at room temperature for 2 hours under a hydrogenatmosphere. After the reaction, the solution was filtrated throughCelite and the solvent was then distilled off, thereby obtaining thesubject compound (382.4 mg) as a white solid.

MS(FAB, Pos.): m/z=396[M+H]⁺

Example 103-8 Synthesis ofN-cyclohexyl-N′-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N′-methyl-butane-1,4-diamine[Compound No. 104]

The compound (110.0 mg) obtained in Example 103-7 was dissolved inanhydrous methanol (4.4 ml). Then, the solution was added withcyclohexanone (0.058 ml) and sodium cyanoborohydride (52.8 mg) andadjusted to pH 5 with acetic acid, followed by stirring at roomtemperature for 16.5 hours. After the reaction, the solvent wasdistilled off. Subsequently, the residue was added with a 1 mol/l sodiumhydroxide aqueous solution (3.0 ml), followed by extraction withchloroform. The extract was dried with magnesium sulfate and the solventwas then distilled off. The residue was purified through silica gelcolumn chromatography (chloroform/methanol) and then treated withhydrochloric acid, thereby obtaining hydrochloride (96.7 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=478[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=1.10–1.12(1H, m), 1.21–1.34(4H, m),1.60–1.67(3H, m), 1.76–1.83(4H, m), 2.02–2.04(2H, m), 2.58(3H, s),2.92–3.01(4H, m), 3.06–3.10(1H, m), 3.72(4H, s), 3.74(2H, s), 4.10(3H,s), 4.18(2H, s), 7.41(2H, d, J=8.2 Hz), 7.46(2H, d, J=8.2 Hz), 7.49(2H,s), 7.61(2H, s).

Production Example 104 Synthesis ofN-(4-dipropylamino-butyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzenesulfonamide[Compound No. 105] Example 104-1 Synthesis ofN-(4-dipropylamino-butyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzenesulfonamide[Compound No. 105]

The compound (76.9 mg) obtained in Example 102-4 was dissolved inanhydrous methanol (3.0 ml). Then, the solution was added withpropionaldehyde (0.039 ml) and sodium cyanoborohydride (45.2 mg) andadjusted to pH 5 with acetic acid, followed by stirring at roomtemperature for 16.5 hours. After the reaction, the solvent wasdistilled off. Subsequently, the residue was added with a 1 mol/l sodiumhydroxide aqueous solution (2.0 ml), followed by extraction withchloroform. The extract was dried with magnesium sulfate and the solventwas then distilled off. The residue was purified through silica gelcolumn chromatography (chloroform/methanol) and then treated withhydrochloric acid, thereby obtaining hydrochloride (36.9 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=516[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.90(6H, t, J=7.3 Hz), 1.44(2H, t, J=7.2Hz), 1.61–1.68(6H, m), 2.69–2.72(2H, m), 2.95–3.03(6H, m), 3.73(3H, s),3.82(2H, s), 4.12(2H, s), 4.19(2H, s), 7.46–7.55(2H, m), 7.57(2H, d,J=8.5 Hz), 7.61(2H, s), 7.67(2H, d, J=8.4 Hz).

Production Example 105 Synthesis ofN-(4-diisobutylamino-butyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzenesulfonamide[Compound No. 106] Example 105-1 Synthesis ofN-(4-diisobutylamino-butyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzenesulfonamide[Compound No. 106]

The compound (86.1 mg) obtained in Example 102-4 was dissolved inanhydrous methanol (3.4 ml). Then, the solution was added withisobutylaldehyde (0.055 ml) and sodium cyanoborohydride (50.3 mg) andadjusted to pH 5 with acetic acid, followed by stirring at roomtemperature for 16.5 hours. After the reaction, the solvent wasdistilled off. Subsequently, the residue was added with a 1 mol/l sodiumhydroxide aqueous solution (2.0 ml), followed by extraction withchloroform. The extract was dried with magnesium sulfate and the solventwas then distilled off. The residue was purified through silica gelcolumn chromatography (chloroform/methanol) and then treated withhydrochloric acid, thereby obtaining hydrochloride (10.1 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=544[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.97(12H, t, J=6.4 Hz), 1.44(2H, t,J=7.2 Hz), 1.65–1.66(2H, m), 2.04(2H, t, J=6.9 Hz), 2.71(2H, t, J=6.7Hz), 2.87–2.94(4H, m), 3.02–3.06(2H, m), 3.72(3H, s), 3.80(2H, s),4.08(2H, s), 4.15(2H, s), 7.46–7.57(4H, m), 7.61(2H, s), 7.67(2H, d,J=8.5 Hz).

Production Example 106 Synthesis of4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-isobutylamino-butyl)-benzenesulfonamide[Compound No. 107] Example 106-1 Synthesis of4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-isobutylamino-butyl)-benzenesulfonamide[Compound No. 107]

The compound (86.1 mg) obtained in Example 102-4 was dissolved inanhydrous methanol (3.4 ml). Then, the solution was added withisobutylaldehyde (0.055 ml) and sodium cyanoborohydride (50.3 mg) andadjusted to pH 5 with acetic acid, followed by stirring at roomtemperature for 16.5 hours. After the reaction, the solvent wasdistilled off. Subsequently, the residue was added with a 1 mol/l sodiumhydroxide aqueous solution (2.0 ml), followed by extraction withchloroform. The extract was dried with magnesium sulfate and the solventwas then distilled off. The residue was purified through silica gelcolumn chromatography (chloroform/methanol) and then treated withhydrochloric acid, thereby obtaining hydrochloride (3.8 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=488[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.94(6H, d, J=6.7 Hz), 1.43–1.46(2H, m),1.63(2H, m), 1.91–1.94(1H, m), 2.67–2.73(4H, m), 2.84–2.87(2H, m),3.71(3H, s), 3.80(2H, s), 4.06(2H, s), 4.12(2H, s), 7.47(2H, d, J=9.6Hz), 7.54(2H, d, J=8.2 Hz), 7.68(2H, d, J=8.4 Hz).

Production Example 107 Synthesis of4-{[bis-(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylamino-butyl)-N-methylbenzamide[Compound No. 108] Example 107-1 Synthesis ofN-methyl-N,N-dipropyl-butan-1,4-diamine

Formic acid (0.29 ml) was added to acetic anhydride (0.60 ml) and thewhole was subjected to thermal reflux for 1.5 hours. After the reaction,the solution was cooled to room temperature. Then, the solution wasadded with THF (2.0 ml) and a solution (8.0 ml) of the compound (400 mg)obtained in Example 1-2 in THF, followed by stirring at room temperaturefor about 4 hours. After the reaction, the solvent was distilled off.

Lithium aluminum hydride (429 mg) was suspended in anhydrous THF (10 ml)and then dropwisely added with a solution (8.0 ml) of thepreviously-obtained compound in anhydrous THF, followed by stirring atroom temperature for 4 hours. Then, the solution was added with sodiumsulfate decahydrate and then added with a 20% sodium hydroxide aqueoussolution. The suspension was filtrated through Celite and the solventwas then distilled off. The residue was purified through silica gelcolumn chromatography (chloroform/ethyl acetate), thereby obtaining thesubject compound (61.8 mg) as a colorless oily substance.

MS(FAB, Pos.): m/z=187[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=0.87(6H, t, J=7.3 Hz), 1.41–1.50(8H, m),2.35–2.42(6H, m), 2.43(3H, s), 2.58(2H, t, J=6.8 Hz).

Example 107-2 Synthesis of4-{[bis-(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylamino-butyl)-N-methylbenzamide[Compound No. 108]

The compound (120 mg) obtained in Example 2-2 was dissolved in DMF (3.5ml). The solution was added with DCC (79.4 mg) and HOBt (62.4 mg),followed by stirring at room temperature for 4 hours. The compound (60.0mg) obtained in Example 107-1 was stirred at room temperature for 86hours. After the reaction, the solvent was distilled off and then theresidue was added with chloroform, followed by extraction with 1 mol/lhydrochloric acid. The extract was made basic with a 1 mol/l sodiumhydroxide aqueous solution, followed by extraction with chloroform.

Subsequently, the extract was dried with magnesium sulfate and thesolvent was then dissolved. The residue was purified through silica gelcolumn chromatography (chloroform/ethyl acetate) and treated withhydrochloric acid, thereby obtaining hydrochloride (10.8 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=480[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+H₂O): δ=0.91(6H, t, J=7.0 Hz), 1.45–1.53(2H, m),1.64–1.67(6H, m), 2.80–3.15(11H, m), 3.72(2H, s), 4.14(2H, s), 7.26(2H,d, J=8.0 Hz), 7.42(2H, 8.0 Hz), 7.57(4H, s).

Production Example 108 Synthesis ofN-[4-(cyclohexyl-methyl-amino)-butyl]-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzenesulfonamide[Compound No. 109] Example 108-1 Synthesis ofN-[4-(cyclohexyl-methyl-amino)-butyl]-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzenesulfonamide[Compound No. 109]

The compound (69.5 mg) obtained in Example 102-5 was treated with ananion-exchange resin (Amberlite IRA-410), and the treated product wasdissolved in anhydrous methanol (2.7 ml). The solution was added with a36% formaldehyde aqueous solution (0.025 ml). Subsequently, the solutionwas added with sodium cyanoborohydride (20.7 mg) and adjusted to pH 5with acetic acid, followed by stirring at room temperature for 20 hours.After the reaction, the solution was added with a 1 mol/l sodiumhydroxide aqueous solution (1.0 ml), followed by extraction withchloroform. The extract was dried with magnesium sulfate. The solventwas distilled off. Then, the residue was purified through silica gelcolumn chromatography (chloroform/methanol) and treated withhydrochloric acid, thereby obtaining hydrochloride (34.8 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=528[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=1.09–1.14(1H, m), 1.23–1.46(6H, m),1.59–1.65(3H, m), 1.79–1.82(2H, m), 1.93–1.97(2H, m), 2.65(3H, s),2.70(2H, t, J=6.6 Hz), 2.89–2.95(1H, m), 3.03–3.12(2H, m), 3.72(3H, s),3.81(2H, s), 4.09(2H, s), 4.16(2H, s), 7.46–7.57(4H, m), 7.60(2H, s),7.67(2H, d, J=8.5 Hz).

Production Example 109 Synthesis of2-[(4-dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-amino]-ethanol[Compound No. 110] Example 109-1 Synthesis of2-[(4-dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-amino]-ethanol[Compound No. 110]

The compound (209.3 mg) obtained in Example 89-2 was dissolved inanhydrous methanol (8.4 ml). Then, the solution was added with[1,4]dioxan-2,5-diol (54.0 mg) and sodium cyanoborohydride (56.6 mg) andadjusted to pH 5 with acetic acid, followed by stirring at roomtemperature for 19.5 hours. After the reaction, the solvent wasdistilled off. Subsequently, the residue was added with a 1 mol/l sodiumhydroxide aqueous solution (1.0 ml), followed by extraction withchloroform. The extract was dried with magnesium sulfate and the solventwas then distilled off. The residue was purified through silica gelcolumn chromatography (chloroform/methanol) and then treated withhydrochloric acid, thereby obtaining hydrochloride (175.8 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=510[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.92(6H, t, J=7.1 Hz), 1.64–1.68(6H, m),1.78–1.82(2H, m), 3.00–3.08(10H, m), 3.71(3H, s), 3.74(4H, s), 4.09(2H,s), 4.17(2H, s), 4.30 (2H, q, J=13.9 Hz), 7.41(2H, d, J=7.8 Hz),7.48(4H, d, J=5.6 Hz), 7.61(2H, s).

Production Example 110 Synthesis of4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-{4-[(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-benzenesulfonamide[Compound No. 111] Example 110-1 Synthesis of4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-{4-[(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-benzenesulfonamide[Compound No. 111]

The compound (102.2 mg) obtained in Example 102-4 was dissolved inanhydrous methanol (4.8 ml) and was then added with the compound (43.6mg) obtained in Example 53-1 and trimethyl orthoformate (0.079 ml),followed by stirring at room temperature for 16 hours. After that, thesolution was cooled with ice and added with sodium borohydride (27.2mg), followed by stirring at room temperature for 2 hours. After thereaction, the solvent was distilled off. The residue was added with a 1mol/l sodium hydroxide aqueous solution (1.0 ml) and then subjected toextraction with chloroform. The extract was dried with magnesiumsulfate. The solvent was distilled off. Then, the residue was purifiedthrough silica gel column chromatography (chloroform/methanol) andtreated with hydrochloric acid, thereby obtaining the hydrochloride(45.9 mg) of the subject compound as a white solid.

MS(FAB, Pos.): m/z=537[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=1.48(2H, t, J=8.1 Hz), 1.71–1.73(2H, m),2.29(3H, s), 2.70(2H, t, J=6.8 Hz), 3.01(2H, t, J=8.1 Hz), 3.72(2H, s),3.81(2H, s), 4.09(2H, s), 4.16(2H, s), 4.32(2H, s), 7.35–7.38(1H, m),7.46–7.56(4H, m), 7.61(2H, d, J=4.6 Hz), 7.68(2H, d, J=8.3 Hz), 7.71(1H.d. J=7.8 Hz), 8.46(1H, d, J=4.2 Hz).

Production Example 111 Synthesis ofN-(4-dipropylamino-butyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-methylbenzamide[Compound No. 112] Example 111-1 Synthesis ofN-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-methylbenzamide

The compound (954.3 mg) obtained in Example 1-1, HOBt (552.1 mg), andDCC (389.2 mg) were dissolved in anhydrous chloroform, followed bystirring at room temperature for 30 minutes. Then, the solution wasadded with the compound (487.8 mg) obtained in Example 107-1, followedby stirring at room temperature for 16 hours. After the reaction, thesolution was washed with water, 1 mol/l hydrochloric acid, and a 1 mol/lsodium hydroxide aqueous solution. The resultant was dried withmagnesium sulfate and the solvent was then distilled off. The residuewas purified through silica gel column chromatography (chloroform/ethylacetate).

The purified product was dissolved in methanol (7.4 ml). A 4 mol/lhydrogen chloride/dioxane solution (7.4 ml) was added to the solution,and the whole was stirred at room temperature for 1.5 hours. After thereaction, the solvent was distilled off. The residue was added with a 1mol/l sodium hydroxide aqueous solution and extracted with chloroform.The extract was dried with magnesium sulfate and the solvent was thendistilled off, thereby obtaining the subject compound (533.8 mg) as awhite solid.

Example 111-2 Synthesis ofN-(4-dipropylamino-butyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-methylbenzamide[Compound No. 112]

The compound (266.9 mg) obtained in Example 111-1 was dissolved inanhydrous methanol (11 ml) and then added with 1-methyl-2-imidazolecarboxaldehyde (110.1 mg) and sodium cyanoborohydride (84.2 mg). Then,the solution was adjusted to pH 5 with acetic acid, followed by stirringat room temperature for 3 days. After the reaction, the solvent wasdistilled off. The residue was added with a 1 mol/l sodium hydroxideaqueous solution (1.0 ml) and extracted with chloroform. The extract wasdried with magnesium sulfate. The solvent was distilled off. Then, theresidue was purified through silica gel column chromatography(chloroform/methanol) and treated with hydrochloric acid, therebyobtaining hydrochloride (234.9 mg) of the subject compound as a whitesolid.

MS(FAB, Pos.): m/z=494[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.91(6H, t, J=7.2 Hz), 1.64(8H, m),2.83(2H, s), 2.94–3.02(6H, m), 3.10(2H, m), 3.71(3H, s), 3.74(2H, s),4.08(2H, s), 4.16(2H, s), 7.27(2H, d, J=7.3 Hz), 7.37(2H, d, J=8.1 Hz),7.50(2H, s), 7.61(2H, s).

Production Example 112 Synthesis ofN-(4-dipropylamino-butyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-methyl-benzenesulfonamide[Compound No. 113] Example 112-1 Synthesis of4-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-N-(4-dipropylamino-butyl)-N-methyl-benzenesulfonamide

The compound (318.3 mg) obtained in Example 24-2 was dissolved inanhydrous dichloromethane (6.4 ml) and added with triethylamine (0.159ml). Then, the mixture was added with the compound (266.5 mg) obtainedin Example 107-1, followed by stirring at room temperature for 2 hours.After the reaction, the solution was washed with water and dried withmagnesium sulfate. The solvent was distilled off and the residue wasthen purified through silica gel column chromatography(chloroform/methanol), thereby obtaining the subject compound (354.4mg).

MS(FAB, Pos.): m/z=486[M+H]⁺

Example 112-2 Synthesis ofN-(4-dipropylamino-butyl)-4-{[(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-methyl-benzenesulfonamide

The compound (354.4 mg) obtained in Example 112-1 was dissolved in a 40%methylamine/methanol solution (3.5 ml), followed by stirring at roomtemperature for 3 days. After the reaction, the solvent was distilledoff and the residue was then dissolved in chloroform, followed bywashing with a 1 mol/l sodium hydroxide aqueous solution. The resultantwas dried with magnesium sulfate, and the solvent was distilled off.

The residue was dissolved in anhydrous methanol (7 ml). Then,2-imidazole carboxaldehyde (105.7 mg) and trimethyl orthoformate (0.24ml) were added to the solution, followed by stirring at room temperaturefor 2 days. After the reaction, the solution was added with sodiumborohydride (82.8 mg) and stirred at room temperature for 24 hours.After the reaction, the solvent was distilled off. The residue was addedwith water and extracted with chloroform. The extract was dried withmagnesium sulfate and the solvent was then distilled off. The residuewas purified through silica gel column chromatography(chloroform/methanol), thereby obtaining the subject compound (171.8mg).

MS(FAB, Pos.): m/z=436[M+H]⁺

Example 112-3 Synthesis ofN-(4-dipropylamino-butyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-methyl-benzenesulfonamide[Compound No. 113]

The compound (171.8 mg) obtained in Example 112-2 was dissolved inanhydrous methanol (7.0 ml). The solution was added with1-methyl-2-imidazole carboxaldehyde (65.0 mg) and sodiumcyanoborohydride (49.0 mg). Then, the solution was adjusted to pH 5 withacetic acid and then stirred at room temperature for 2 days. After thereaction, the solvent was distilled off. The residue was added with a 1mol/l sodium hydroxide aqueous solution and extracted with chloroform.The extract was dried with magnesium sulfate, and the solvent wasdistilled off. Then, the residue was purified through silica gel columnchromatography (chloroform/methanol) and treated with hydrochloric acid,thereby obtaining hydrochloride (184.8 mg) of the subject compound as awhite solid.

MS(FAB, Pos.): m/z=530[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.92(6H, t, J=7.3 Hz), 1.55(2H, t, J=7.0Hz), 1.64–1.69(6H, m), 2.61(3H, s), 2.92(2H, t, J=6.7 Hz), 3.00–3.01(4H,m), 3.06–3.09(2H, m), 3.73(3H, s), 3.83(2H, s), 4.12(2H, s), 4.19(2H,s), 7.48–7.51(2H, m), 7.57–7.65(6H, m).

Production Example 113 Synthesis ofN-(4-di-n-propylaminomethyl-phenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1H-[1,2,4]-triazol-3-ylmethyl)-amino]-methyl}-benzamide[Compound No. 114] Example 113-1 Synthesis ofN-(4-di-n-propylaminomethyl-phenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1H-[1,2,4]-triazol-3-ylmethyl)-amino]-methyl}-benzamide[Compound No. 114]

The compound (100.0 mg) obtained in Example 47-3 was dissolved inmethanol (3.0 ml). Then, the solution was added with1H-[1,2,4]-triazol-3-carboxaldehyde (51.0 mg) synthesized by the methoddescribed in Heterocycles (vol. 15, No. 1, page 1981) and sodiumcyanoborohydride (30.0 mg). Subsequently, the solution was adjusted topH 5 with acetic acid and stirred at room temperature for 17 hours.After completion of the reaction, the reaction solution was added with a1 mol/l sodium hydroxide aqueous solution and then subjected toseparation/extraction with a mixture solution of chloroform/methanol.The organic layer was dried with anhydrous sodium sulfate and thesolvent was then distilled off. The residue was purified through silicagel column chromatography (chloroform/methanol) and treated withhydrochloric acid, thereby obtaining hydrochloride (37.4 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=501[M+H]⁺

¹H-NMR(500 Mz, DMSO-d₆+D₂O): δ=0.88(6H, t, J=7.3 Hz), 1.60–1.78(4H, m),2.92–3.00(4H, m), 3.78(2H, s), 3.87(2H, s), 4.11(2H, s), 4.28(2H, s),7.53(2H, d, J=8.7 Hz), 7.56(2H, s), 7.57(2H, d, J=8.2 Hz), 7.87(2H, d,J=8.7 Hz), 7.92(2H, d, J=8.2 Hz), 8.49(1H, brs).

Production Example 114 Synthesis of[4-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzimidazol-2-yl)-butyl]-dipropylamine[Compound No. 115] Example 114-1 Synthesis of4-amino-3-{(5-t-butoxycarbonylamino)pentanoyl}aminobenzoic acid methylester

In DMF 20 ml, 5-t-butoxycarbonyl aminovaleric acid (1.45 g), WSCIhydrochloride (1.74 g), and HOBt (1.25 g) were dissolved, followed bystirring for 15 minutes. Then, the solution was added with methyl3,4-diaminobenzoate (1.00 g) and stirred at room temperature for 4hours. After completion of the reaction, the solvent was distilled offunder reduced pressure. The residue was dissolved in chloroform and thenwashed with a saturated aqueous ammonium chloride solution and a 1 mol/lsodium hydroxide aqueous solution. Subsequently, the resultant wassubjected to extraction with chloroform and the extract was then washedwith saturated saline solution, followed by drying with anhydrous sodiumsulfate. After filtration, the solvent was distilled off under reducedpressure. The residue was purified through silica gel columnchromatography (chloroform/ethyl acetate), thereby obtaining the subjectcompound (1.46 g).

MS(FAB, Pos.): m/z=365[M+H]

Example 114-2 Synthesis of2-(4-dipropylaminobutyl)-3H-benzimidazole-5-carboxylic acid methyl ester

4-amino-3-{(5-t-butoxycarbonylamino)pentanoyl}aminobenzoic acid methylester (1.46 g) was dissolved in methanol (7.3 ml) and then added with a4 mol/l hydrogen chloride/dioxane solution (7.3 ml), followed bystirring overnight at 40° C. After completion of the reaction, thesolvent was distilled off under reduced pressure and the residue wasdried under vacuum. The dried product was dissolved in methanol (15 ml)and added with triethylamine (0.597 ml), trimethyl orthoformate (1 ml),and propionaldehyde (0.309 ml), followed by stirring at room temperaturefor 30 minutes. The solution was added with sodium cyanoborohydride (272mg) and stirred at room temperature for 30 minutes. Furthermore, thesolution was added with propionaldehyde (0.310 ml) and sodiumcyanoborohydride (270 mg), followed by stirring at room temperature for4 hours. After completion of the reaction, the solvent was distilled offunder reduced pressure. The residue was dissolved in chloroform and thenwashed with a 1 mol/l sodium hydroxide aqueous solution, followed byextraction with chloroform. The organic layer was washed with saturatedsaline solution and then dried with anhydrous sodium sulfate. Afterfiltration, the solvent was distilled off under reduced pressure and theresidue was then purified through silica gel column chromatography(chloroform/ethyl acetate), thereby obtaining the subject compound (315mg) as a brown viscous substance.

MS(FAB, Pos.): m/z=332[M+H]⁺

Example 114-3 Synthesis of{4-[6-chloromethyl-1-(toluene-4-sulfonyl)-1H-benzimidazol-2-yl]butyl}dipropylamine

Lithium aluminum hydride (108 mg) was suspended in THF (60 ml) anddropwisely added with a solution (60 ml) of the compound (315 mg)obtained in Example 114-2 in THF, followed by stirring at roomtemperature for 1 hour. After completion of the reaction, sodium sulfatedecahydrate was added to the solution until bubbling was not observed,and a 1 mol/l sodium hydroxide aqueous solution was then gradually addedto the mixture until a white precipitate was generated. Afterfiltration, the solvent was distilled off under reduced pressure. Theresidue was dried under vacuum, and the dried product was dissolved indichloromethane (10 ml) and then added with triethylamine (263 μl) andp-toluenesulfonyl chloride (364 mg), followed by stirring at roomtemperature for 2.5 hours. After completion of the reaction, thesolution was washed with water and extracted with chloroform. Theorganic layer was washed with saturated saline solution and then driedwith anhydrous sodium sulfate. After filtration, the solvent wasdistilled off under reduced pressure and the residue was then purifiedthrough silica gel column chromatography (chloroform/methanol), therebyobtaining the subject compound (113 mg) as a brown solid.

MS(FAB, Pos.): m/z=476[M+H]⁺

Example 114-4 Synthesis of[4-(6-aminomethyl-1H-benzimidazol-2-yl)butyl]dipropylamine

The compound (113 mg) obtained in Example 114-3 was dissolved in DMF (2ml) and added with potassium phthalimide (69.0 mg), followed by stirringat room temperature for 2 days. After completion of the reaction, thesolvent was distilled off under reduced pressure and the residue wasthen dissolved in chloroform, followed by washing with water. Afterextraction with chloroform, the organic layer was washed with saturatedsaline solution and dried with anhydrous sodium sulfate. Afterfiltration, the solvent was distilled off under reduced pressure. Theresidue was dried under vacuum, and the dried product was dissolved in a40% methylamine/methanol solution (1.5 ml), followed by stirringovernight at room temperature. After completion of the reaction, thesolvent was distilled off under reduced pressure and the residue wasthen dissolved in chloroform, followed by washing with water and a 1mol/l sodium hydroxide aqueous solution. After extraction withchloroform, the extract was washed with saturated saline solution anddried with anhydrous sodium sulfate. After filtration, the solvent wasdistilled off under reduced pressure and the residue was then purifiedthrough silica gel column chromatography (chloroform/methanol), therebyobtaining the subject compound (39.8 mg) as a brown solid.

MS(FAB, Pos.): m/z=303[M+H]⁺

Example 114-5 Synthesis of[4-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzimidazol-2-yl)-butyl]-dipropylamine[Compound No. 115]

The compound (39.8 mg) obtained in Example 114-4 was dissolved inmethanol (1.0 ml) and then added with 2-imidazole carboxaldehyde (13.3mg) and trimethyl orthoformate (0.030 ml), followed by stirring at roomtemperature for 30 minutes. The solution was gradually added with sodiumborohydride (10.5 mg), followed by stirring at room temperature for 1hour. After completion of the reaction, the solvent was distilled offunder reduced pressure and the residue was then dissolved in chloroform.After having been washed with water, the solution was extracted withchloroform. The organic layer was washed with saturated saline solutionand then dried with anhydrous sodium sulfate. After filtration, thesolvent was distilled off under reduced pressure. Subsequently, theresidue was dissolved in methanol (1.0 ml) and added with1-methyl-2-imidazole carboxaldehyde (63.2 mg), acetic acid (0.023 ml),trimethyl orthoformate (0.030 ml), and sodium cyanoborohydride (23.2mg), followed by stirring at room temperature for 30 minutes. Thesolution was added with acetic acid (0.045 ml) and stirred at roomtemperature for 4 hours. After completion of the reaction, the solventwas distilled off under reduced pressure and the residue was thendissolved in chloroform. After having been washed with a 1 mol/l sodiumhydroxide aqueous solution, the solution was extracted with chloroform.The organic layer was washed with saturated saline solution and thendried with anhydrous sodium sulfate. After filtration, the solvent wasdistilled off under reduced pressure. Subsequently, the residue waspurified through silica gel column chromatography (chloroform/methanol)and treated with hydrochloric acid, thereby obtaining hydrochloride(27.6 mg) of the subject compound as a white solid.

MS(FAB, Pos.): m/z=477[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.89(3H, t, J=7.3 Hz), 1.63–1.69(4H, m),1.70–1.81(2H, m), 1.94–2.01(2H, m), 2.84–3.00(4H, m), 3.03–3.09(2H, m),3.19–3.23(2H, m), 3.72(3H, s), 3.90(2H, s), 4.13(2H, s), 4.21(2H, s),4.41(2H, t, J=7.3 Hz), 7.49(1H, s), 7.53(1H, s), 7.59(1H, d, J=8.4 Hz),7.64–7.66(3H, m), 7.81(1H, s), 10.50(1H, s).

Production Example 115 Synthesis ofN-(4-{[(imidazol-2-ylmethyl)-([1,2,4]-triazol-3-ylmethyl)-amino]-methyl}-benzyl)-N-methyl-N′,N′-dipropylbutane-1,4-diamine[Compound No. 116] Example 115-1 Synthesis of{4-[(4-dipropylamino-butylamino)-methyl]-benzyl}-carbamic acid t-butylester

The compound (225.3 mg) obtained in Example 103-3 was dissolved inmethanol (6.76 ml). Then, the solution was added with the compound(165.0 mg) obtained in Example 1-2 and trimethyl orthoformate (304.8mg), followed by stirring at room temperature for 18 hours. Sodiumborohydride (108.7 mg) was added to the solution under ice-cooling,followed by stirring at room temperature for 0.5 hours. The reactionsolution was added with water and subjected to separation/extractionwith chloroform. Then, the extract was washed with saturated salinesolution and dried with anhydrous sodium sulfate, followed byconcentration under reduced pressure. The residue was purified throughsilica gel column chromatography (chloroform/methanol), therebyobtaining the subject compound (297.6 mg) as a colorless oily substance.

Example 115-2 Synthesis of(4-{[(4-dipropylamino-butyl)-methyl-amino]-methyl}-benzyl)-carbamic acidt-butyl ester

The compound (625.7 mg) obtained in Example 115-1 was dissolved inmethanol (25.0 ml) and added with a 36% formaldehyde aqueous solution(0.246 ml) and sodium cyanoborohydride (220.9 mg). The solution wasadjusted to pH 5 with acetic acid and stirred at room temperature for 27hours. The reaction solution was concentrated under reduced pressure andthe residue was added with a 1 mol/l sodium hydroxide aqueous solution,followed by separation/extraction with chloroform. After having beenwashed with saturated saline solution, the extract was dried withanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified through silica gel column chromatography(chloroform/ethyl acetate), thereby obtaining the subject compound(648.1 mg) as a colorless oily substance.

Example 115-3 Synthesis ofN-(4-aminomethyl-benzyl)-N-methyl-N,N′-dipropyl-butan-1,4-diamine

The compound (0.956 g) obtained in Example 115-2 was dissolved inmethanol (9.56 ml) and added with a 4 mol/l hydrogen chloride/dioxanesolution (19.1 ml) and stirred at room temperature for 1 hour. After thereaction solution had been concentrated under reduced pressure, theresidue was added with a 1 mol/l sodium hydroxide aqueous solution andsubjected to separation/extraction with chloroform. Then, the organiclayer was washed with saturated saline solution and dried with anhydroussodium sulfate. Then, the dried product was concentrated under reducedpressure and dried under vacuum, thereby obtaining the subject compound(0.720 g) as a colorless oily substance.

Example 115-4 Synthesis ofN-(4-{[(imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N-methyl-N,N′-dipropyl-butan-1,4-diamine

The compound (336.5 mg) obtained in Example 115-3 was dissolved inmethanol and added with 2-imidazole carboxaldehyde (158.8 mg) andtrimethyl orthoformate (350.7 mg), followed by stirring at roomtemperature for 17 hours. Sodium borohydride (125.0 mg) was added to thesolution under ice-cooling, and the whole was stirred at roomtemperature for 1.5 hours. The reaction solution was concentrated underreduced pressure. The residue was added with water and then subjected toseparation/extraction with chloroform. The organic layer obtained wasdried with anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified through silica gel columnchromatography (chloroform/methanol), thereby obtaining the subjectcompound (409.7 mg) as a colorless oily substance.

Example 115-5 Synthesis ofN-(4-{[(imidazol-2-ylmethyl)-([1,2,4]-triazol-3-ylmethyl)-amino]-methyl}-benzyl)-N-methyl-N′,N′-dipropylbutane-1,4-diamine[Compound No. 116]

The compound (409.7 mg) obtained in Example 115-4 was dissolved inmethanol (12.3 ml) and added with 1H-[1,2,4]-triazol-3-carboxaldehyde(206.3 mg) and sodium cyanoborohydride (133.5 mg). Then, the solutionwas adjusted to pH 5 with acetic acid and stirred at room temperaturefor 38 hours. The reaction solution was concentrated under reducedpressure. Subsequently, the residue was then purified through silica gelcolumn chromatography (chloroform/methanol) and treated withhydrochloric acid, thereby obtaining hydrochloride (105.6 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=467[M+H]⁺

Production Example 116 Synthesis ofN-methyl-N-(4-{[(1-methyl-imidazol-2-ylmethyl)-([1,2,4]-triazol-3-ylmethyl)-amino]-methyl}-benzyl)-N′,N′-dipropyl-butane-1,4-diamine[Compound No. 117] Example 116-1 Synthesis ofN-methyl-N-(4-{[(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N,N′-diamine

The compound (336.5 mg) obtained in Example 115-3 was dissolved inmethanol (10.1 ml) and added with 1-methyl-2-imidazole carboxaldehyde(181.9 mg) and trimethyl orthoformate (350.7 mg), followed by stirringat room temperature for 17 hours. Sodium borohydride (125.0 mg) wasadded to the solution under ice-cooling, and then the whole was stirredat room temperature for 1.5 hours. The reaction solution wasconcentrated under reduced pressure and the residue was then added withwater, followed by separation/extraction with chloroform. The organicsolvent obtained was dried with anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified throughsilica gel column chromatography (chloroform/methanol), therebyobtaining the subject compound (440.2 mg) as a colorless oily substance.

Example 116-2 Synthesis ofN-methyl-N-(4-{[(1-methyl-imidazol-2-ylmethyl)-([1,2,4]-triazol-3-ylmethyl)-amino]-methyl}-benzyl)-N′,N′-dipropyl-butane-1,4-diamine[Compound No. 117]

The compound (440.2 mg) obtained in Example 116-1 was dissolved inmethanol (13.2 ml) and added with 1H-[1,2,4]-triazol-3-carboxaldehyde(213.9 mg) and sodium cyanoborohydride (138.4 mg). Then, the solutionwas adjusted to pH 5 with acetic acid and stirred at room temperaturefor 38 hours. The reaction solution was concentrated under reducedpressure. Subsequently, the residue was then purified through silica gelcolumn chromatography (chloroform/methanol) and treated withhydrochloric acid, thereby obtaining hydrochloride (197.0 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=481[M+H]⁺

Production Example 117 Synthesis ofN-(4-dipropylaminomethylbenzyl)-N′-(1H-imidazol-2-ylmethyl)-N′-(1-methyl-1H-imidazol-2-ylmethyl)-1,4-butanediamine[Compound No. 118] Example 117-1 Synthesis of 4-dipropylaminomethylbenzaldehyde

The compound (443 mg) obtained in Example 80-2 was dissolved indichloromethane (9.0 ml) and added with manganese (IV) oxide (chemicallytreated product, manufactured by Wako Pure Chemical Industries, Ltd.)(873 mg), followed by stirring at room temperature for 5 hours. Aftercompletion of the reaction, the solution was filtrated through Celiteand the filtrate was then concentrated under reduced pressure. Theresidue was purified through silica gel column chromatography(chloroform/ethyl acetate), thereby obtaining the subject compound (397mg) as a brown solid.

MS(FAB, Pos.): m/z=220[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=0.86(6H, t, J=7.3 Hz), 1.47(4H, sext., J=7.3Hz), 2.36(4H, t, J=7.3 Hz), 3.54(2H, s), 3.91(3H, s), 7.30(2H, d, J=8.3Hz), 7.33(2H, d, J=8.3 Hz).

Example 117-2 Synthesis of 4-(1H-imidazol-2-ylmethyl)aminobutyl carbamicacid t-butyl

In methanol (3 ml), 4-aminobutyl carbamic acid t-butyl (202 mg),2-imidazole carboxaldehyde (152 mg) was dissolved, and trimethylorthoformate (0.20 ml) were added to the solution. Then, the mixture wasstirred at room temperature for 1.5 hours. After having been cooled to0° C., the solution was added with sodium borohydride (81.1 mg) andstirred at 0° C. for 2 hours, followed by stirring at room temperaturefor an additional one hour. After completion of the reaction, thesolvent was distilled off under reduced pressure. The residue wasdissolved in chloroform and washed with a 1 mol/l sodium hydroxideaqueous solution. After extraction with chloroform, the organic layerwas washed with saturated saline solution and dried with anhydroussodium sulfate. Subsequently, the solvent was distilled off and theresidue was then dried under vacuum, thereby obtaining the subjectcompound (334 mg) as a white solid.

MS(FAB, Pos.): m/z=269[M+H]⁺

Example 117-3 Synthesis of4-[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)]aminobutylcarbamic acid t-butyl

The compound (334 mg) obtained in Example 117-2 was dissolved inmethanol (4 ml) and added with 1-methyl-2-imidazole carboxaldehyde (175mg) and acetic acid (0.2 ml), followed by cooling to 0° C. Sodiumcyanoborohydride (133 mg) was added to the solution, and the whole wasstirred overnight at room temperature. After completion of the reaction,the solvent was distilled off under reduced pressure. The residue wasdissolved in chloroform and then washed with a 1 mol/l sodium hydroxideaqueous solution. After extraction with chloroform, the organic layerwas washed with saturated saline solution and dried with anhydroussodium sulfate. After filtration, the solvent was distilled off underreduced pressure and the residue was then dried under vacuum, therebyobtaining the subject compound (429 mg) as a white solid.

MS(FAB, Pos.): m/z=363[M+H]⁺

Example 117-4 Synthesis ofN-(1H-imidazol-2-ylmethyl)-N-(1-methyl-1H-imidazol-2-ylmethyl)butane-1,4-diamine

The compound (429 mg) obtained in Example 117-3 was dissolved inmethanol (4.0 ml) and added with a 4 mol/l hydrogen chloride/dioxanesolution (4.0 ml), followed by stirring at room temperature for 2 hours.After completion of the reaction, the solvent was distilled off underreduced pressure. The residue was dissolved in methanol and neutralizedwith an anion-exchange resin (Amberlite IRA-410). Subsequently, thesolvent was distilled off and the residue was then dried under vacuum,thereby obtaining the subject compound (349 mg) as a pale-yellow solid.

MS(FAB, Pos.): m/z=263[M+H]⁺

Example 117-5 Synthesis ofN-(4-dipropylaminomethylbenzyl)-N′-(1H-imidazol-2-ylmethyl)-N′-(1-methyl-1H-imidazol-2-ylmethyl)-1,4-butanediamine[Compound No. 118]

The compound (349 mg) obtained in Example 117-4 was dissolved inmethanol (7.0 ml). Then, the solution was added with the compound (323mg) obtained in Example 117-1 and trimethyl orthoformate (0.340 ml) andstirred at room temperature for 2 hours, followed by cooling to 0° C.The solution was added with sodium borohydride (75.5 mg) and stirred atroom temperature for 30 minutes. After completion of the reaction, thesolvent was distilled off under reduced pressure. The residue wasdissolved in chloroform and washed with an aqueous sodium bicarbonatesolution, followed by extraction with chloroform. The organic layer waswashed with saturated saline solution and then dried with anhydroussodium sulfate. After filtration, the solvent was distilled off underreduced pressure. The residue was purified through silica gel columnchromatography (chloroform) and treated with hydrochloric acid, therebyobtaining hydrochloride (89.8 mg) of the subject compound as a whitesolid.

MS(FAB, Pos.): m/z=466[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.85(6H, t, J=7.3 Hz), 1.51–1.55(2H, m),1.61–1.64(2H, m), 1.67–1.79(4H, m), 2.47(2H, t, J=7.3 Hz), 2.80(2H, br),2.84–2.92(4H, m), 3.81(3H, s), 4.12(4H, s), 4.17(2H, s), 4.31(2H, d,J=5.5 Hz), 7.61(1H, s), 7.62–7.73(7H, m), 9.57(2H, brs), 11.08(1H, brs).

Production Example 118 Synthesis ofN-(4-dipropylaminomethylbenzyl)-N′-(1H-imidazol-2-ylmethyl)-N-methyl-N′-(1-methyl-1H-imidazol-2-ylmethyl)-butane-1,4-diamine[Compound No. 119] Example 118-1 Synthesis ofN-(4-dipropylaminomethylbenzyl)-N′-(1H-imidazol-2-ylmethyl)-N-methyl-N′-(1-methyl-1H-imidazol-2-ylmethyl)-butane-1,4-diamine[Compound No. 119]

The hydrochloride (39.4 mg) of the compound obtained in Example 117-5was dissolved in methanol (1.0 ml) and added with triethylamine (0.050ml), trimethyl orthoformate (0.040 ml), and a 36% formaldehyde solution(0.020 ml), followed by stirring at room temperature for 2 hours. Thesolution was gradually added with sodium borohydride (15.0 mg) afterhaving been cooled to 0° C., and then warmed to room temperature,followed by stirring for 1 hour. After completion of the reaction, thesolvent was distilled off under reduced pressure. The residue wasdissolved in chloroform and washed with a 1 mol/l sodium hydroxideaqueous solution, followed by extraction with chloroform. The organiclayer was washed with saturated saline solution and dried with anhydroussodium sulfate. After filtration, the solvent was distilled off underreduced pressure. Then, the residue was purified through silica gelcolumn chromatography (chloroform/methanol) and treated withhydrochloric acid, thereby obtaining hydrochloride (28.2 mg) of thesubject compound as a white solid.

MS(FAB, Pos.) m/z=480[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.85(6H, t, J=7.3 Hz), 1.40–1.52(2H, br),1.66–1.76(6H, m), 2.44–2.52(2H, m), 2.60(3H, s), 2.84–3.04(6H, br),3.81(3H, s), 4.11(2H, s), 4.15(2H, s), 4.20–4.44(4H, m), 7.63(1H, s),7.67–7.75(7H, m), 10.95(2H, br).

Production Example 119 Synthesis of[3-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-quinolin-2-yl)-propyl]-dipropylamine[Compound No. 120] Example 119-1 Synthesis of 6-bromomethyl-2-methylquinoline

In carbon tetrachloride (26 ml), 2,6-dimethylquinoline (manufactured byTokyo Kasei Kogyo Co., Ltd.) (1.0398 g), N-bromosuccinimide (1.2353 g),and azobisisobutyronitrile (98.5 mg) were dissolved and then the wholewas subjected to thermal reflux for 2 hours under an argon atmosphere.After the reaction, a precipitate was removed through filtration andthen washed with water, followed by drying with magnesium sulfate. Thesolvent was distilled off and the residue was then purified throughsilica gel column chromatography (hexane/ethyl acetate), therebyobtaining the subject compound (427.3 mg) as a white solid.

MS(FAB, Pos.): m/z=236, 238[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=2.66(3H, s), 4.90(2H, s), 7.44(1H, d, J=8.4Hz), 7.75(1H, dd, J=2.1, 8.7 Hz), 7.91(1H, d, J=8.5 Hz), 7.99(1H, d,J=2.0 Hz), 8.24(1H, d, J=8.4 Hz).

Example 119-2 Synthesis of2-(2-methylquinolin-6-ylmethyl)-isoindole-1,3-dione

The compound (421.7 mg) obtained in Example 119-1 was dissolved inanhydrous DMF (12.6 ml) and added with potassium phthalimide (663.1 mg),followed by stirring at room temperature for 2 hours. After thereaction, the solvent was distilled off and the residue was then addedwith water. The mixture was extracted with chloroform and the extractwas dried with magnesium sulfate. The solvent was distilled off and theresidue was then purified through silica gel column chromatography(chloroform/ethyl acetate), thereby obtaining the subject compound(536.0 mg) as a white solid.

MS(FAB, Pos.): m/z=303[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=2.63(3H, s), 4.95(2H, s), 7.39(1H, d, J=8.4Hz), 7.66(1H, dd, J=2.1, 8.7 Hz), 7.81(1H, d, J=10.4 Hz), 7.86–7.89(3H,m), 7.92–7.94(2H, m), 8.22(1H, d, J=8.4 Hz).

Example 119-3 Synthesis of2-(2-methyl-1-oxy-quinolin-6-ylmethyl)-isoindole-1,3-dione

The compound (534.7 mg) obtained in Example 119-2 was dissolved inchloroform (16 ml) and then added with meta-chloroperbenzoic acid (321.0mg), followed by stirring at room temperature for 4 hours. Furthermore,meta-chloroperbenzoic acid (153.6 mg) was added to the solution, and thewhole was stirred at room temperature for 1 hour. The solution waswashed with a saturated sodium bicarbonate solution and dried withmagnesium sulfate. The solvent was distilled off and the residue wasthen purified through silica gel column chromatography(chloroform/methanol), thereby obtaining the subject compound (511.8 mg)as a white solid.

MS(FAB, Pos.): m/z=319[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=2.54(3H, s), 4.97(2H, s), 7.56(1H, d, J=8.5Hz), 7.75(1H, dd, J=2.0, 9.0 Hz), 7.82(1H, d, J=8.8 Hz), 7.87–7.90(2H,m), 7.92–7.96(3H, m), 8.51(1H, d, J=8.8 Hz).

Example 119-4 Synthesis of2-(2-hydroxymethyl-quinolin-6-ylmethyl)-isoindole-1,3-dione

The compound (510.6 mg) obtained in Example 119-3 was dissolved indichloromethane (5.1 ml). Under ice-cooling, the solution was added withtrifluoroacetic anhydride (0.452 ml) and stirred at room temperature for2 hours. After the solvent had been distilled off, methanol (10 ml) anda saturated sodium bicarbonate solution (10 ml) were added to theresidue, and the whole was stirred at room temperature for 1 hour. Afterthe reaction, the solvent was distilled off. The residue was extractedwith chloroform and the extract was dried with magnesium sulfate. Afterthe solvent had been distilled off, the residue was purified throughsilica gel column chromatography (chloroform/methanol), therebyobtaining the subject compound (458.2 mg) as a white solid.

MS(FAB, Pos.): m/z=319[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=4.70(2H, d, J=6.0 Hz), 5.00(2H, s), 5.56(1H,t, J=6.0 Hz), 7.63(1H, d, J=8.5 Hz), 7.69(1H, dd, J=2.1, 8.7 Hz),7.86–7.89(3H, m), 7.91–7.95(3H, m), 8.34(1H, d, J=8.4 Hz).

Example 119-5 Synthesis of6-(1,3-dioxy-1,3-dihydro-isoindol-2-ylmethyl)-quinoline-2-carboxaldehyde

The compound (457.4 mg) obtained in Example 119-4 was dissolved inchloroform (7 ml) and then added with manganese dioxide (chemicallyprocessed product) (2.4556 g), followed by stirring at room temperaturefor 3.5 hours. After the reaction, the solution was filtrated throughCelite. The solvent was distilled off and the residue was then purifiedthrough silica gel column chromatography (chloroform/ethyl acetate),thereby obtaining the subject compound (366.9 mg) as a white solid.

MS(FAB, Pos.): m/z=317[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=5.03(2H, s), 7.87–7.90(3H, m), 7.93–7.98(3H,m), 8.04(1H, d, J=1.2 Hz), 8.21(1H, d, J=8.7 Hz), 8.58(1H, d, J=8.7 Hz),10.11(1H, s).

Example 119-6 Synthesis of3-[6-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-quinolin-2-yl]-acrylonitrile

The compound (153.8 mg) obtained in Example 119-5,(triphenylphosphanylidene)-acetonitrile (manufactured by AldrichCorporation) (183.3 mg), and anhydrous THF (9.2 ml) were admixedtogether and stirred at room temperature for 2 hours. After thereaction, the solvent was distilled off under reduced pressure. Theresidue was purified through silica gel column chromatography(hexane/ethyl acetate), thereby obtaining the subject compound (164.2mg) as a yellow solid.

MS(FAB, Pos.): m/z=340[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=5.00(2H, d, J=5.4 Hz), 6.18(1H, d, J=12.0Hz), 6.91(1H, d, J=16.4 Hz), 7.60(1H, d, J=11.7 Hz), 7.79–7.95(6H, m),8.00(1H, d, J=8.5 Hz), 8.49(1H, d, J=8.3 Hz).

Example 119-7 Synthesis of3-[6-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-quinolin-2-yl]-propionitrile

The compound (574.4 mg) obtained in Example 119-6 was dissolved inethanol (20 ml) and chloroform (10 ml). Then, the solution was addedwith 20% palladium hydroxide-carbon (172.3 mg) and then stirred at roomtemperature for 16 hours under a hydrogen atmosphere. After thereaction, the solution was filtrated through Celite and the solvent wasthen distilled off under reduced pressure. The residue was purifiedthrough silica gel column chromatography (hexane/ethyl acetate), therebyobtaining the subject compound (101.9 mg) as a yellow solid.

MS(FAB, Pos.): m/z=342[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=3.02(2H, t, J=7.3 Hz), 3.26(2H, t, J=7.3Hz), 4.97(2H, s), 7.49(1H, d, J=8.5 Hz), 7.71(1H, dd, J=2.2, 8.7 Hz),7.86–7.88(3H, m), 7.92–7.94(2H, m), 8.31(1H, d, J=8.5 Hz).

Example 119-8 Synthesis of[2-(2-cyano-ethyl)-quinolin-6-ylmethyl]-carbamic acid t-butyl ester

The compound (181.2 mg) obtained in Example 119-7 was dissolved in a 40%methylamine/methanol solution (3.6 ml) and stirred at room temperaturefor 21 hours. After the reaction, the solvent was distilled off underreduced pressure. The residue was dissolved in chloroform and thenwashed with a 1 mol/l sodium hydroxide aqueous solution, followed bydrying with magnesium sulfate. The solvent was distilled off underreduced pressure. Then, the residue was dissolved in chloroform (5.1 ml)and then added with di-t-butyl dicarbonate (174.6 mg) and triethylamine(0.112 ml), followed by stirring overnight at room temperature. Aftercompletion of the reaction, the solvent was distilled off under reducedpressure and the residue was then purified through silica gel columnchromatography (chloroform/ethyl acetate), thereby obtaining the subjectcompound (139.9 mg) as a yellow solid.

MS(FAB, Pos.): m/z=312[M+H]⁺

Example 119-9 Synthesis of[2-(3-dipropylamino-propyl)-quinolin-6-ylmethyl]-carbamic acid t-butylester

The compound (139.9 mg) obtained in Example 119-8 was dissolved inanhydrous THF (4.2 ml). Then, lithium aluminum hydride (68.3 mg) wasadded to the solution, followed by stirring at room temperature for 2hours. The solution was added with an aqueous potassium sodium tartratesolution and stirred at room temperature. After completion of thereaction, extraction with chloroform was carried out. The organic layerwas dried with magnesium sulfate and the solvent was then distilled offunder reduced pressure. The residue was added with anhydrous methanol(4.1 ml), propionaldehyde (0.095 ml), trimethyl orthoformate (0.144 ml),and sodium cyanoborohydride (110.6 mg) and stirred at room temperaturefor 2 hours. After completion of the reaction, the solvent was distilledoff under reduced pressure. Then, the residue was dissolved inchloroform and washed with water, followed by drying with magnesiumsulfate. The solvent was distilled off under reduced pressure. Theresidue was purified through silica gel column chromatography(toluene/ethyl acetate), thereby obtaining the subject compound (62.6mg) as a yellow solid.

MS(FAB, Pos.): m/z=400[M+H]⁺

Example 119-10 Synthesis of[3-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-quinolin-2-yl)-propyl]-dipropylamine[Compound No. 120]

The compound (62.6 mg) obtained in Example 119-9 was dissolved inmethanol (1.2 ml). Then, a 4 mol/l hydrogen chloride/dioxane solution(1.2 ml) was added to the solution, and the whole was stirred at roomtemperature for 2 hours. After the solution had been subjected to ananion-exchange resin (Amberlite IRA-410), the solvent was distilled offunder reduced pressure. The residue was dissolved in anhydrous methanol(1.0 ml) and added with 2-imidazole carboxaldehyde (25.0 mg) andtrimethyl orthoformate (0.056 ml), followed by stirring at roomtemperature for 16 hours. Then, sodium borohydride (19.3 mg) was addedto the solution, and the whole was stirred at room temperature for 6hours. After the reaction, the solvent was distilled off under reducedpressure and the residue was added with water, followed by extractionwith chloroform. Subsequently, the extract was then dried with magnesiumsulfate, followed by distilling the solvent off. The residue wasdissolved in anhydrous methanol (2.3 ml) and then added with1-methyl-2-imidazole carboxaldehyde (28.6 mg) and sodiumcyanoborohydride (32.0 mg). Then, the solution was adjusted to about pH5 with acetic acid, followed by stirring at room temperature for 16hours. After completion of the reaction, the solvent was distilled offunder reduced pressure. Then, the residue was dissolved in chloroformand washed with a 1 mol/l sodium hydroxide aqueous solution. Thesolution was dried with magnesium sulfate and the solvent was thendistilled off under reduced pressure. The residue was purified throughsilica gel column chromatography (chloroform/ethyl acetate) and treatedwith hydrochloric acid, thereby obtaining hydrochloride (19.6 mg) of thesubject compound as a pale-yellow solid.

MS(FAB, Pos.): m/z=474[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.92(6H, t, J=7.3 Hz), 1.63–1.71(4H, m),2.19–2.22(2H, m), 3.02–3.06(4H, m), 3.13–3.19(4H, m), 3.72(3H, s),3.95(2H, s), 4.13(2H, s), 4.20(2H, s), 7.46(2H, s), 7.60(2H, s),7.75(1H, d, J=8.8 Hz), 7.94(1H, d, J=8.1 Hz), 8.04(1H, d, J=9.0 Hz),8.10(1H, br), 8.62(1H, d, J=8.8 Hz).

Production Example 120 Synthesis of[3-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzo[b]-thiophen-2-yl)-propyl]-dipropyl-amine[Compound No. 121] Example 120-1 Synthesis of5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzo[b]thiophene-2-carboxylicacid ethyl ester

In carbon tetrachloride (100 ml),5-methyl-benzo[b]thiophene-2-carboxylic acid ethyl ester (2.36 g)prepared by the method described in PCT Patent WO 0153291 was dissolved.The solution was added with N-bromosuccinimide (2.00 g) andazobisisobutyronitrile (140.7 mg), and the whole was stirred for 17hours under thermal reflux. After the insoluble matter had been removedthrough filtration, the residue was recrystallized with methanol. Then,the crystal was dissolved in DMF (20 ml) and then added with potassiumphthalimide (1.18 g), followed by stirring overnight at roomtemperature. After the solvent had been distilled off, the residue wasadded with water and extracted with chloroform. The organic layer waswashed with saturated saline solution and dried with anhydrous sodiumsulfate, thereby obtaining the subject compound (1.15 g) as apale-yellow solid.

Example 120-2 Synthesis of(2-hydroxymethyl-benzo[b]thiophen-5-ylmethyl)-carbamic acid t-butylester

The compound (1.05 g) obtained in Example 120-1 was dissolved inmethanol (20 ml) and added with hydrazine monohydrate (1.0 ml), followedby thermal reflux for 3 hours. The solution was added with water andsubjected to extraction with chloroform. The resulting organic layer waswashed with saturated saline solution and then dried with anhydroussodium sulfate. The dried product was dissolved in DMF (30 ml) and thenadded with triethylamine (0.60 ml) and di-t-butyl dicarbonate (942.8mg), followed by stirring overnight at room temperature. After thesolvent had been distilled off, the residue was added with water andextracted with chloroform. The organic layer was washed with saturatedsaline solution and then dried with anhydrous sodium sulfate. The driedproduct was dissolved in anhydrous THF (10 ml). The solution wasgradually dropped in a solution cooled at 0° C., which was prepared bysuspending lithium aluminum hydride (218.6 mg) in anhydrous THF (20 ml),over 5 minutes, followed by stirring at 0° C. for 1 hour. Ethyl acetateand methanol were added to the solution, and the whole was concentrated.The residue was then purified through silica gel column chromatography(chloroform/methanol), thereby obtaining the subject compound (600.0 mg)as a white solid.

MS(FAB, Pos.): m/z=294[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=1.40(9H, s), 4.21(2H, s), 4.73(2H, s),7.19–7.21(1H, m), 7.24(1H, s), 7.60(1H, s), 7.84(1H, d, J=8.3 Hz).

Example 120-3 Synthesis of3-[5-(t-butoxycarbonylamino-methyl)-benzo[b]thiophen-2-yl]-acrylic acidmethyl ester

The compound (596.0 mg) obtained in Example 120-2 was dissolved inanhydrous chloroform (30 ml). Then, the solution was added withmanganese dioxide (chemically processed product) (6.0 g), followed bystirring at room temperature for 15.5 hours. Insoluble matter wasfiltrated and the filtrate was then dissolved in anhydrous THF (20 ml).Subsequently, the solution was added with methyltriphenylphosphoranilideneacetate (814.5 mg), followed by stirring atroom temperature for 22 hours. The solvent was distilled off and theresidue was then purified through silica gel column chromatography(hexane/ethyl acetate), thereby obtaining the subject compound (560.0mg) as a white solid.

MS(FAB, Pos.): m/z=348[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=1.40(9H, s), 3.74(3H, s), 4.22(2H, s),6.32(1H, d, J=15.8 Hz), 7.34(1H, dd, J=1.5 Hz,8.3 Hz), 7.71(1H, s),7.85(1H, s), 7.90–7.93(1H, m), 7.96(1H, s).

Example 120-4 Synthesis of3-[5-(t-butoxycarbonylamino-methyl)-benzo[b]thiophen-2-yl]-acrylic acidmethyl ester

The compound (560.0 mg) obtained in Example 120-3 was dissolved inmethanol (50 ml) and chloroform (30 ml) and then added with 10%palladium-carbon (56 mg), followed by stirring for 2.5 hours under ahydrogen atmosphere. After the catalyst had been filtrated, the filtratewas dissolved in anhydrous THF (10 ml) and then gradually added to asolution cooled at 0° C., which was prepared by suspending lithiumaluminum hydride (2.12 g) in anhydrous THF 20 ml, over 5 minutes,followed by stirring at 0° C. for 1 hour and then stirring at roomtemperature for 1.5 hours. After the addition of ethyl acetate andmethanol, the solvent was distilled off and the residue was thenpurified through silica gel column chromatography (chloroform/methanol),thereby obtaining the subject compound (380.0 mg) as a white solid.

MS(FAB, Pos.): m/z=322[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=1.39(9H, s), 1.80–1.86(2H, m),2.91–2.94(2H, m), 3.46–3.48(2H, m), 4.20(2H, s), 7.31(1H, dd, J=1.3Hz,8.4 Hz), 7.56(1H, s), 7.79(1H, d, J=8.3 Hz).

Example 120-5 Synthesis of[2-(3-dipropylamino-propyl)-benzo[b]thiophen-5-ylmethyl]-carbamic acidt-butyl ester

The compound (356.0 mg) obtained in Example 120-4 was dissolved inanhydrous dichloromethane (10 ml) and added with Dess-Martin periodinane(manufactured by Aldrich Corporation) (563.7 mg), followed by stirringat room temperature for 40 minutes. Then, the solution was added withwater and extracted with chloroform. The organic layer was washed withsaturated saline solution and dried with anhydrous sodium sulfate. Thesolvent was distilled off and the residue was then purified throughsilica gel column chromatography (hexane/ethyl acetate). The purifiedproduct was dissolved in methanol (10 ml) and then added withdi-n-propylamine (0.19 ml), trimethyl orthoformate (0.15 ml), and sodiumcyanoborohydride (87.6 mg), followed by stirring at room temperature for30 hours. The solution was added with water and then extracted withchloroform. The organic layer was washed with saturated saline solutionand then dried with anhydrous sodium sulfate. Subsequently, the solventwas distilled off and the residue was purified through silica gel columnchromatography (hexane/ethyl acetate), thereby obtaining the subjectcompound (241.9 mg) as a pale-yellow solid.

MS(FAB, Pos.): m/z=405[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.84(6H, t, J=7.3 Hz), 1.39(9H, s),1.77–1.80(2H, m), 2.30–2.33(4H, m), 2.40–2.43(2H, m), 2.88–2.91(2H, m),4.20(2H, s), 7.12(1H, s), 7.17(1H, dd, J=1.5 Hz,8.2 Hz), 7.56(1H, s),7.89(1H, d, J=8.2 Hz).

Example 120-6 Synthesis of[3-(5-{[(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzo[b]thiophen-2-yl)-propyl]-dipropyl-amine

The compound (237.7 mg) obtained in Example 120-5 was added to a 4 mol/lhydrogen chloride/dioxane solution (4.74 ml) and the whole was stirredfor 17 hours. Then, the solvent was distilled off, and the residue wasdried. The dried product was dissolved in methanol and then neutralizedwith an anion-exchange resin (Amberlite IRA-410). Subsequently, thesolvent was distilled off and the residue was then dried under reducedpressure. After the dried product had been dissolved in methanol (8 ml),2-imidazole carboxaldehyde (84.6 mg) and trimethyl orthoformate (0.19ml) were added to the solution, and then the whole was stirred at roomtemperature for 20 hours. Subsequently, sodium borohydride (66.6 mg) wasadded to the solution, and then the whole was stirred at roomtemperature for 16 hours. After completion of the reaction, the solutionwas added with water and subjected to chloroform extraction. Theresulting organic layer was washed with saturated saline solution,followed by drying with anhydrous sodium sulfate. The solvent wasdistilled off and the residue was then purified through silica gelcolumn chromatography (chloroform/methanol), thereby obtaining thesubject compound (197.9 mg) as a white yellow solid.

MS(FAB, Pos.): m/z=385[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.84(6H, t, J=7.3 Hz), 1.35–1.39(4H, m),1.77–1.80(2H, m), 2.30–2.33(4H, m), 2.41–2.44(2H, m), 2.88–2.91(2H, m),3.69(2H, s), 3.74(2H, s), 6.83(1H, brs), 7.04(1H, brs), 7.11(1H, s),7.26(1H, dd, J=1.7, 8.4 Hz), 7.67(1H, s), 7.79(1H, d, J=8.2 Hz).

Example 120-7 Synthesis of[3-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzo[b]-thiophen-2-yl)-propyl]-dipropyl-amine[Compound No. 121]

The compound (197.9 mg) obtained in Example 120-6 was dissolved inmethanol (10 ml) and then added with 1-methyl-2-imidazole carboxaldehyde(68.0 mg) and sodium cyanoborohydride (64.7 mg). After that, thesolution was adjusted to pH 5 with acetic acid, followed by stirringovernight at room temperature. After the solvent had been distilled off,the residue was purified through silica gel column chromatography(chloroform/methanol) and treated with hydrochloric acid, therebyobtaining hydrochloride (228.7 mg) of the subject compound as a whitesolid.

MS(FAB, Pos.): m/z=479[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.90(6H, t, J=7.2 Hz), 1.16–1.19(2H, m),1.62–1.67(4H, m), 1.99(3H, s), 2.01–2.10(4H, m), 2.95–3.03(6H, m),3.09–3.12(2H, m), 3.70(2H, s), 3.80(2H, s), 4.01–4.08(4H, m), 4.15(2H,s), 7.20(1H, s), 7.31(1H, dd, J=1.4 Hz,8.3 Hz), 7.48(1H, s), 7.61(1H,s), 7.76(1H, s), 7.80(1H, d, J=8.4 Hz).

Production Example 121 Synthesis of2-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-6-(3-dipropylaminopropyl)-naphtalene[Compound No. 122] Example 121-1 Synthesis of2,6-dihydroxymethylnaphthalene

2,6-naphthalene dicarboxylic acid dimethyl (5.00 g) was dissolved inanhydrous THF (150 ml) and added with lithium aluminum hydride (1.55 g)under ice-cooling, followed by stirring at room temperature for 2 hoursunder a nitrogen atmosphere. After completion of the reaction, methanoland an aqueous potassium sodium tartrate solution were added to thesolution in this order and the whole was stirred overnight. The solutionwas subjected to extraction with chloroform and ethyl acetate and theextract was then washed with saturated saline solution. Subsequently,the organic layer was dried with anhydrous sodium sulfate and thesolvent was distilled off, thereby obtaining the subject compound (3.90g) as a white solid.

¹H-NMR(500 MHz, CDCl₃): δ=4.87(4H, d, J=6.4 Hz), 7.50(2H, dd, J=1.5, 7.3Hz), 7.83(2H, d, J=8.3 Hz), 7.84(2H, d, J=8.3 Hz).

Example 121-2 Synthesis of2-t-butyldimethylsilyloxymethyl-6-hydroxymethylnaphthalene

The compound (3.41 g) obtained in Example 121-1 was dissolved inanhydrous DMF (200 ml). Then, t-butyldimethylsilyl chloride (2.73 g)dissolved in imidazole (1.48 g) and anhydrous DMF (50 ml) was dropped inthis solution, and the whole was stirred overnight at room temperature.After completion of the reaction, the solution was added with asaturated aqueous ammonium chloride solution and stirred. The solutionwas extracted with chloroform and the extract was then washed with asaturated aqueous sodium bicarbonate solution, a saturated aqueousammonium chloride solution, and saturated saline solution. Then, theorganic layer was dried with anhydrous sodium sulfate. Subsequently, thesolvent was distilled off and the residue was then purified throughsilica gel column chromatography (chloroform), thereby obtaining thesubject compound (2.68 g) as a white solid.

¹H-NMR(500 MHz, CDCl₃): δ=0.13(6H, s), 0.97(9H, s), 1.74(1H, t, J=5.9Hz), 4.86(2H, d, J=5.9 Hz), 4.90(2H, s), 7.44(1H, dd, J=1.5, 8.3 Hz),7.48(1H, dd, J=2.0, 8.8 Hz), 7.77(1H, s), 7.80(2H, d, J=8.3 Hz),7.83(1H, d, J=8.8 Hz).

Example 121-3 Synthesis of2-t-butyldimethylsilyloxylmethylnaphthalene-6-carboxaldehyde

The compound (255 mg) obtained in Example 121-2 was dissolved inchloroform (5.0 ml) and then added with manganese dioxide (chemicallyprocessed product) (366 mg), followed by stirring overnight at roomtemperature. After completion of the reaction, the solution wasfiltrated through Celite and the solvent was then distilled off, therebyobtaining the subject compound (245 mg) as a white solid.

Example 121-4 Synthesis of3-(2-t-butyldimethylsilyloxylmethylnaphthalen-6-yl)acrylic acid methylester

The compound (245 mg) obtained in Example 121-3 was dissolved inanhydrous THF (5.0 ml), added with methyltriphenylphophoranylideneacetate (300 mg), and stirred at roomtemperature for 5 days under a nitrogen atmosphere. After completion ofthe reaction, the solvent was distilled off and the residue was thenpurified through silica gel column chromatography (hexane/ethylacetate), thereby obtaining the subject compound (223 mg) as a whitesolid.

MS(FAB, Pos.): m/z=357[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=0.14(6H, s), 0.97(9H, s), 3.83(3H, s),4.90(2H, s), 6.55(1H, d, J=16.1 Hz), 7.46(1H, dd, J=1.7, 8.5 Hz),7.66(1H, dd, J=1.7, 8.5 Hz), 7.77(1H, s), 7.82(2H, dd, J=3.4, 8.5 Hz),7.85(1H, d, J=16.1 Hz), 7.91(1H, s).

Example 121-5 Synthesis of3-(6-t-butyldimethylsilyloxymethylnaphthalen-2-yl)propionic acid methylester

The compound (2.54 g) obtained in Example 121-4 was dissolved inanhydrous benzene (80 ml) and added with palladium black, followed bystirring at room temperature for 1 hour under a nitrogen atmosphere.After completion of the reaction, the solution was filtrated throughCelite. Then, the solvent was distilled off, thereby obtaining thesubject compound (2.62 g) as a white solid.

¹H-NMR(500 MHz, CDCl₃): δ=0.12(6H, s), 0.96(9H, s), 2.72(2H, t, J=7.6Hz), 3.11(2H, t, J=7.6 Hz), 3.68(3H, s), 4.88(2H, s), 7.32(1H, dd,J=2.0, 8.5 Hz), 7.41(1H, dd, J=1.7, 8.5 Hz), 7.62(1H, s), 7.73(1H, s),7.76(2H, d, J=8.1 Hz).

Example 121-6 Synthesis of3-(6-t-butyldimethylsilyloxymethylnaphthalen-2-yl)propan-1-ol

The compound (2.62 g) obtained in Example 121-5 was dissolved inanhydrous THF (100 ml) and added with lithium aluminum hydride (555 mg)under ice-cooling, followed by stirring for 30 minutes under a nitrogenatmosphere. After completion of the reaction, the solution was addedwith methanol and then added with an aqueous potassium sodium tartratesolution, followed by stirring overnight. The solution was extractedwith chloroform and the extract was washed with saturate salinesolution. Then, the organic layer was dried with anhydrous sodiumsulfate. The solvent was distilled off, thereby obtaining the subjectcompound (2.64 g) as a white solid.

¹H-NMR(500 MHz, CDCl₃): δ=0.13(6H, s), 0.97(9H, s), 1.96–2.02(2H, m),2.87(2H, t, J=7.3 Hz), 3.71(2H, q, J=6.3 Hz), 4.89(2H, s), 7.34(1H, dd,J=1.7, 8.3 Hz), 7.41(1H, dd, J=1.7, 8.3 Hz), 7.62(1H, s), 7.74(2H, d,J=8.3 Hz), 7.76(1H, d, J=8.3 Hz).

Example 121-7 Synthesis of3-(6-t-butyldimethylsilyloxymethylnaphthalen-2-yl)propionaldehyde

The compound (1.18 g) obtained in Example 121-6 was dissolved inanhydrous dichloromethane (25 ml) and added with Dess-Martin periodinane(1.82 g), followed by stirring at room temperature for 2 hours. Aftercompletion of the reaction, a sodium thiosulfate aqueous solution and asaturated aqueous sodium bicarbonate solution were added to thesolution, and the whole was stirred. Then, the solution was extractedwith chloroform and the extract was then washed with an aqueous mixturesolution of a sodium thiosulfate aqueous solution and a saturated sodiumbicarbonate aqueous solution. Then, the organic layer was dried withanhydrous sodium sulfate and the solvent was distilled off. The residuewas purified through silica gel column chromatography (hexane/ethylacetate), thereby obtaining the subject compound (981 mg) as a whitesolid.

¹H-NMR(500 MHz, CDCl₃): δ=0.13(6H, s), 0.96(9H, s), 2.88(2H, dt, J=1.7,7.6 Hz), 3.12(2H, t, J=7.6 Hz), 4.88(2H, s), 7.32(1H, dd, J=2.0, 8.3Hz), 7.41(1H, dd, J=1.7, 8.8 Hz), 7.61(1H, s), 7.73(1H, s), 7.74(1H, d,J=7.8 Hz), 7.76(1H, d, J=8.3 Hz), 9.87(1H, s).

Example 121-8 Synthesis of[3-(6-t-butyldimethylsilyloxymethylnaphthalen-2-yl)propyl]dipropylamine

Dipropylamine (363 mg) was dissolved in anhydrous methanol (20 ml) andthen added with sodium cyanoborohydride (281 mg), trimethyl orthoformate(0.490 ml), and the compound (981 mg) obtained in Example 121-7,followed by stirring overnight at room temperature under a nitrogenatmosphere. After completion of the reaction, the solvent was distilledoff. Then, the residue was dissolved in chloroform and added with asaturated aqueous sodium bicarbonate solution, followed by stirring. Thesolution was extracted with chloroform and the extract was then washedwith a saturated aqueous sodium bicarbonate solution and saturatedsaline solution. After that, the organic layer was dried with anhydroussodium sulfate. Subsequently, the solvent was distilled off and theresidue was then purified through silica gel column chromatography(chloroform/ethyl acetate), thereby obtaining the subject compound (1.28g) as a brown liquid.

MS(FAB, Pos.): m/z=414[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=0.16(6H, s), 0.87(6H, t, J=7.3 Hz), 0.96(9H,s), 1.45(4H, sext., J=7.6 Hz), 1.86(2H, quint., J=7.8 Hz), 2.38(4H, t,J=7.6 Hz), 2.49(2H, t, J=7.8 Hz), 2.77(2H, t, J=7.8 Hz), 4.88(2H, s),7.33(1H, dd, J=1.7, 8.4 Hz), 7.40(1H, dd, J=1.7, 8.1 Hz), 7.60(1H, s),7.73(1H, s), 7.73(1H, d, J=8.4 Hz), 7.74(1H, d, J=8.5 Hz).

Example 121-9 Synthesis of2-hydroxymethyl-6-(3-dipropylaminopropyl)naphthalene

The compound (1.28 g) obtained in Example 121-8 was added with a 1 mol/lTBAF/THF solution (6.20 ml) and stirred overnight at room temperature.After completion of the reaction, the solvent was distilled off. Then,the residue was dissolved in chloroform and added with distilled water,followed by stirring. The solution was extracted with chloroform and theextract was then washed with saturated saline solution. The resultingorganic layer was dried with anhydrous sodium sulfate. Subsequently, thesolvent was distilled off and the residue was then purified throughsilica gel column chromatography (chloroform/ethyl acetate), therebyobtaining the subject compound (472 mg) as a brown liquid.

MS(FAB, Pos.): m/z=300[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=0.87(6H, t, J=7.6 Hz), 1.44(4H, sext., J=7.6Hz), 1.86(2H, quint., J=7.1 Hz), 2.38(4H, t, J=7.6 Hz), 2.49(2H, t,J=7.1 Hz), 2.78(2H, t, J=7.8 Hz), 4.85(2H, s), 7.35(1H, dd, J=2.0, 8.5Hz), 7.46(1H, dd, J=1.7, 8.5 Hz), 7.62(1H, s), 7.76(1H, d, J=9.3 Hz),7.78(1H, s), 7.78(1H, d, J=9.3 Hz).

Example 121-10 Synthesis of2-phthalimidomethyl-6-(3-dipropylaminopropyl)naphthalene

The compound (453 mg) obtained in Example 121-9 was added withtriphenylphosphine (516 mg) and phthalimide (245 mg), and then dissolvedin anhydrous THF (10 ml). The solution was added with a 40%diethylazodicarboxylate/toluene solution (0.892 ml) in an ice bath andstirred at room temperature for 2 hours under a nitrogen atmosphere.After completion of the reaction, the solvent was distilled off and theresidue was then purified through silica gel column chromatography(hexane/ethyl acetate), thereby obtaining the subject compound (439 mg)as a white solid.

MS(FAB, Pos.): m/z=429[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=0.86(6H, t, J=7.6 Hz), 1.42(4H, sext., J=7.6Hz), 1.82(2H, quint., J=7.6 Hz), 2.35(4H, t, J=7.6 Hz), 2.45(2H, t,J=7.6 Hz), 2.75(2H, t, J=7.6 Hz), 4.99(2H, s), 7.32(1H, dd, J=1.7, 8.5Hz), 7.52(1H, dd, J=2.0, 8.5 Hz), 7.57(1H, s), 7.70–7.74(4H, m),7.84–7.87(3H, m).

Example 121-11 Synthesis of2-aminomethyl-6-(3-dipropylaminopropyl)naphthalene

The compound (439 mg) obtained in Example 121-10 was dissolved in a 40%methylamine/methanol solution (45 ml) and stirred at room temperaturefor 3 days. After completion of the reaction, the solvent was distilledoff. Then, a 1 mol/l sodium hydroxide aqueous solution was added to theresidue, and the whole was stirred. The solution was extracted withchloroform and the extract was washed with saturated saline solution.After that, the organic layer was dried with anhydrous sodium sulfate.Then, the solvent was distilled off, thereby obtaining the subjectcompound (283 mg) as a colorless oily substance.

MS(FAB, Pos.): m/z=299[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=0.87(6H, t, J=7.3 Hz), 1.44(4H, sext., J=7.6Hz), 1.85(2H, quint., J=7.8 Hz), 2.37(4H, t, J=7.6 Hz), 2.48(2H, t,J=7.8 Hz), 2.77(2H, t, J=7.8 Hz), 4.02(2H, s), 7.34(1H, dd, J=1.7, 8.3Hz), 7.41(1H, dd, J=2.0, 8.5 Hz), 7.60(1H, s), 7.71(1H, s), 7.74(1H, d,J=8.3 Hz), 7.75(1H, d, J=8.1 Hz).

Example 121-12 Synthesis of2-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-6-(3-dipropylaminopropyl)-naphtalene[Compound No. 122]

The compound (280 mg) obtained in Example 121-11 was dissolved inanhydrous methanol (5.0 ml) and added with trimethyl orthoformate (0.154ml) and 2-imidazole carboxaldehyde (90.1 mg), followed by stirring atroom temperature for 2 hours under a nitrogen atmosphere. Subsequently,the solution was added with sodium borohydride (53.3 mg) in an ice bathand stirred at room temperature for 30 minutes. After completion of thereaction, a saturated aqueous ammonium chloride solution was added tothe solution, and the whole was stirred. The solution was subjected toextraction with chloroform. The extract was washed with a saturatedaqueous sodium bicarbonate solution and saturated saline solution. Then,the organic layer was dried with anhydrous sodium sulfate. The residueobtained was dissolved in anhydrous methanol (10 ml) and added withsodium cyanoborohydride (93.6 mg), acetic acid (3.00 ml), and1-methyl-2-imidazole carboxaldehyde (120 mg), followed by stirring atroom temperature for 2 days under a nitrogen atmosphere. Aftercompletion of the reaction, the solvent was distilled off and theresidue was then dissolved in chloroform. The solution was added with asaturated aqueous sodium bicarbonate solution and stirred. The solutionwas subjected to extraction with chloroform and the extract was thenwashed with a saturated aqueous sodium bicarbonate solution andsaturated saline solution. The organic layer was dried with anhydroussodium sulfate and then the solvent was distilled off. Subsequently, theresidue was purified through silica gel column chromatography(chloroform/ethyl acetate) and treated with hydrochloric acid, therebyobtaining hydrochloride (318 mg) of the subject compound as a whitesolid.

MS(FAB, Pos.): m/z=473[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.89(6H, t, J=7.3 Hz), 1.62(4H, sext.,J=7.3 Hz), 2.03(2H, quint. 7.9 Hz), 2.79(2H, t, J=7.8 Hz), 2.99–3.02(4H,m), 3.09(2H, t, J=8.1 Hz), 3.85(2H, s), 4.10(2H, s), 4.18(2H, s),7.43(1H, d, J=1.8 Hz), 7.44(1H, s), 7.45(1H, d, J=1.8 Hz), 7.50(1H, d,J=8.4 Hz), 7.59(2H, d, J=1.4 Hz), 7.71(1H, s), 7.77(1H, d, J=8.5 Hz),7.83(1H, s), 7.83(1H, d, J=8.4 Hz).

Production Example 122 Synthesis ofN-(4-di-n-propylaminomethyl-phenyl)-4-{[(1-methyl-imidazol-2-ylmethyl)-(1H-[1,2,4]-triazol-3-ylmethyl)-amino]-methyl}-benzamide[Compound No. 123] Example 122-1 Synthesis of4-(t-butoxycarbonylaminomethyl)-benzoic acid

Commercially available 4-aminomethylbenzoic acid/hydrochloride (20.9 g)was dissolved in dioxane (200 ml), water (100 ml), and a 1 mol/l sodiumhydroxide aqueous solution (137.9 ml). Then, under ice-cooling,di-t-butyl dicarbonate (30.7 g) was added to the solution. The reactionsolution was stirred at room temperature for 17 hours and thenconcentrated under reduced pressure. The residue was added with a 1mol/l sodium hydroxide aqueous solution and water, and then added with 1mol/l hydrochloric acid to adjust the solution to pH 4. The precipitatedsolid was separated through filtration and heated and dried underreduced pressure, thereby obtaining the subject compound (31.3 g) as awhite solid.

Example 122-2 Synthesis of[4-(4-dipropylaminomethyl-phenylcarbamoyl)-benzyl]-carbamic acid t-butylester

The compound (1.95 g) obtained in Example 122-1 was dissolved inchloroform (20 ml) and DMF (8 ml) and then added with WSCI hydrochloride(1.50 g) and HOBt (1.08 g), followed by stirring at room temperature for1 hour. The compound (1.23 g) obtained in Example 19-2 and chloroform(10 ml) were added to the solution, and the whole was stirred at roomtemperature for 15 hours. The reaction solution was concentrated underreduced pressure and the residue was then purified through silica gelcolumn chromatography (chloroform/methanol), thereby obtaining thesubject compound (2.86 g) as a yellow oily substance.

Example 122-3 Synthesis of4-aminomethyl-N-(4-dipropylaminomethyl-phenyl)-benzamide

The compound (1.38 g) obtained in Example 122-2 was dissolved inmethanol (10 ml), added with a 4 mol/l hydrogen chloride/dioxanesolution (15 ml), and stirred at room temperature for 30 minutes. Thereaction solution was concentrated under reduced pressure andneutralized with an anion-exchange resin (Amberlite IRA-410). Thesolvent was concentrated under reduced pressure and the residue wasdried under vacuum, thereby obtaining the subject compound (0.79 g) as ayellow solid.

Example 122-4 Synthesis ofN-(4-dipropylaminomethyl-phenyl)-4-{[(1-methyl-1H-imidazol-2-ylmethyl)-amino]methyl}benzamide

The compound (290.2 mg) obtained in Example 122-3 was dissolved inmethanol (8.71 ml) and added with 1-methyl-2-imidazole carboxaldehyde(141.2 mg) and trimethyl orthoformate (272.2 mg), followed by stirringfor 22 hours. The reaction solution was cooled with ice and then addedwith sodium borohydride (97.0 mg), followed by stirring at roomtemperature for 0.5 hour. The reaction solution was concentrated underreduced pressure and the residue was then added with water, followed byseparation/extraction with chloroform. The organic layer was washed withsaturate saline solution and dried with anhydrous sodium sulfate,followed by concentration under reduced pressure. The residue waspurified through silica gel column chromatography (chloroform/methanol),thereby obtaining the subject compound (256.8 mg) as a yellow oilysubstance.

Example 122-5 Synthesis ofN-(4-di-n-propylaminomethyl-phenyl)-4-{[(1-methyl-imidazol-2-ylmethyl)-(1H-[1,2,4]-triazol-3-ylmethyl)-amino]-methyl}-benzamide[Compound No. 123]

The compound (256.8 mg) obtained in Example 122-4 was dissolved inmethanol (7.7 ml) and added with 1H-[1,2,4]-triazol-3-carboxaldehyde(115.0 mg) and sodium cyanoborohydride (74.4 mg). Then, the solution wasadjusted to pH 5 with acetic acid and stirred at room temperature for 14hours. The reaction solution was concentrated under reduced pressure.Subsequently, the residue was purified through silica gel columnchromatography (chloroform/methanol) and treated with hydrochloric acid,thereby obtaining hydrochloride (337.9 mg) of the subject compound as awhite solid.

¹H-NMR(500 Mz, DMSO-d₆+D₂O): δ=0.88(6H, t, J=7.3 Hz), 1.62–1.76(4H, m),2.92–2.98(4H, m), 3.77(3H, s), 3.81(2H, s), 3.92(2H, s), 4.11(2H, s),4.28(2H, s), 7.47–7.52(3H, m), 7.56(2H, d, J=8.5 Hz), 7.88(2H, d, J=8.5Hz), 7.92(2H, d, J=8.3 Hz), 8.66(1H, brs).

Production Example 123 Synthesis of[5-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-quinolin-2-yl)-pentyl]-dipropylamine[Compound No. 124] Example 123-1 Synthesis of(3-cyano-propyl)-triphenyl-phosphonium bromide

Triphenylphosphine (1.4789 g) was dissolved in anhydrous toluene (44.4ml) and then added with 4-bromo-butyronitrile (manufactured by TokyoKasei Kogyo Co., Ltd.) (834.7 mg), followed by thermal reflux for 22hours. After the reaction, a precipitated product was filtrated. Theprecipitate obtained through filtration was washed with toluene andthermally dried under reduced pressure, thereby obtaining the subjectcompound (1.1697 g) as a white solid.

¹H-NMR(500 MHz, DMSO-d₆): δ=1.87(2H, dt, J=7.3, 11.7 Hz), 2.72(2H, t,J=7.3 Hz), 3.63–3.70(2H, m), 7.76–7.84(12H, m), 7.90–7.94(3H, m).

Example 123-2 Synthesis of5-[6-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-quinolin-2-yl]-penta-4-ennitrile

The compound (675.0 mg) obtained in Example 123-1 was suspended inanhydrous THF (30 ml) and cooled with ice. Then, the suspension wasadded with a 2 mol/l lithium diisopropylamide/heptane solution (0.825ml), followed by stirring at room temperature for 1 hour. Then, thesolution was gradually added with a solution prepared by suspending thecompound (327.9 mg) obtained in Example 119-7 in anhydrous THF (20 ml),followed by stirring at room temperature for 3 hours. After completionof the reaction, the solvent was distilled off and the residue was thenpurified through silica gel column chromatography (chloroform/ethylacetate), thereby obtaining the subject compound (268.0 mg) as a yellowsolid.

MS(FAB, Pos.): m/z=368[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=2.66(2H, t, J=7.3 Hz), 3.19(2H, dq, J=1.5, 7.3Hz), 5.03(2H, s), 6.03–6.08(1H, m), 6.69(1H, dt, J=1.5, 10.0 Hz),7.29(1H, d, J=8.5 Hz), 7.71–7.75(2H, m), 7.77(1H, dd, J=2.0, 8.8 Hz),7.83(1H, d, J=1.7 Hz), 7.86–7.89(2H, m), 7.98(1H, d, J=8.5 Hz), 8.08(1H,d, J=8.3 Hz).

Example 123-3 Synthesis of[2-(4-cyano-butyl)-quinolin-6-ylmethyl]-carbamic acid t-butyl ester

The compound (265.1 mg) obtained in Example 123-2 was dissolved in a 40%methylamine/methanol solution (8.0 ml) and then stirred at roomtemperature for 15 hours. After the reaction, the solvent was distilledoff under reduced pressure. The residue was dissolved in chloroform andthen washed with a 1 mol/l sodium hydroxide aqueous solution. Theresultant was dried with magnesium sulfate and the solvent was thendistilled off under reduced pressure.

The residue was dissolved in chloroform (5.1 ml) and added withdi-t-butyl dicarbonate (235.7 mg) and triethylamine (0.151 ml), followedby stirring at room temperature for 5 hours. After the reaction, thesolvent was distilled off under reduced pressure.

The residue was dissolved in ethanol (12 ml) and then added with 20%palladium hydroxide-carbon (242.9 mg), followed by stirring at roomtemperature for 1.5 hours under a hydrogen atmosphere. After thereaction, the solution was filtrated through Celite and the solvent wasthen distilled off. The residue was purified through silica gel columnchromatography (hexane/ethyl acetate), thereby obtaining the subjectcompound (82.0 mg) as a yellow solid.

MS(FAB, Pos.): m/z=340[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=1.48(9H, s), 1.78(1H, quint., J=7.3 Hz),1.98–2.05(2H, m), 2.41(2H, t, J=7.3 Hz), 3.02(2H, t, J=7.6 Hz), 4.50(2H,d, J=5.9 Hz), 4.97(1H, br), 7.29(1H, d, J=8.3 Hz), 7.62(1H, d, J=8.8Hz), 7.67(1H, s), 7.99(1H, d, J=8.5 Hz), 8.05(1H, d, J=8.3 Hz).

Example 123-4 Synthesis of[2-(5-dipropylamino-pentyl)-quinolin-6-ylmethyl]-carbamic acid t-butylester

The compound (75.8 mg) obtained in Example 123-3 was dissolved inanhydrous THF (2.2 ml). Then, the solution was added with lithiumaluminum hydride (33.4 mg) and stirred at room temperature for 1 hour.An aqueous potassium sodium tartrate solution was added in thissolution, and the whole was stirred, followed by extraction withchloroform. The organic layer was dried with magnesium sulfate and thesolvent was then dried off. The residue was dissolved in anhydrousmethanol (2.3 ml) and added with propionaldehyde (0.048 ml), trimethylorthoformate (0.072 ml), and sodium cyanoborohydride (55.3 mg), followedby stirring at room temperature for 19 hours. The solvent was distilledoff. Subsequently, the solvent was purified through silica gel columnchromatography (hexane/ethyl acetate), thereby obtaining the subjectcompound (56.6 mg) as a yellow solid.

MS(FAB, Pos.): m/z=428[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=0.85(6H, t, J=7.3 Hz), 1.38–1.51(8H, m),1.48(9H, s), 1.82(2H, quint., J=7.8 Hz), 2.34–2.37(4H, m), 2.40(2H, t,J=7.3 Hz), 2.96(2H, t, J=7.8 Hz), 4.49(2H, d, J=5.9 Hz), 4.95–4.98(1H,br), 7.29(1H, d, J=8.3 Hz), 7.61(1H, d, J=8.3 Hz), 7.66(1H, s), 8.00(1H,d, J=8.5 Hz), 8.03(1H, d, J=8.3 Hz).

Example 123-5 Synthesis of[5-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino)-methyl}-quinolin-2-yl)-pentyl]-dipropylamine[Compound No. 124]

The compound (52.6 mg) obtained in Example 123-4 was dissolved inmethanol (1.6 ml) and added with a 4 mol/l hydrogen chloride/dioxanesolution (1.6 ml), followed by stirring at room temperature for 1.5hours. After the reaction, the solvent was distilled off under reducedpressure. The residue was neutralized with an anion-exchange resin(Amberlite IRA-410) and the solvent was then distilled off. The residuewas dissolved in anhydrous methanol (1.0 ml) and added with 2-imidazolecarboxaldehyde (17.3 mg). The mixture was stirred at room temperaturefor 2 hours and then added with sodium borohydride (13.6 mg), followedby stirring at room temperature for 4 hours. After completion of thereaction, the solvent was distilled off and the residue was thendissolved in chloroform, followed by washing with water. The organiclayer was dried with magnesium sulfate and the solvent was thendistilled off. The residue was dissolved in anhydrous methanol (1.0 ml)and added with 1-methyl-2-imidazole carboxaldehyde (19.8 mg) and sodiumcyanoborohydride (22.6 mg). The resulting solution was adjusted to pH 5with acetic acid and then stirred at room temperature for 14 hours.After completion of the reaction, chloroform was added to the solution,followed by washing with a 1 mol/l sodium hydroxide aqueous solution.The organic layer was dried with magnesium sulfate and the solvent wasthen distilled off under reduced pressure. The residue was purifiedthrough silica gel column chromatography (chloroform/methanol) andtreated with hydrochloric acid. Consequently, hydrochloride (45.4 mg) ofthe subject compound was obtained as a white solid.

MS(FAB, Pos.): m/z=502[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆+D₂O): δ=0.91(6H, t, J=7.3 Hz), 1.39(2H, t, J=7.8Hz), 1.60–1.73(6H, m), 1.82–1.88(2H, m), 2.97–3.09(6H, m), 3.16(2H, t,J=8.1 Hz), 3.73(3H, s), 3.97(2H, s), 4.13(2H, s), 4.20(2H, s), 7.46(2H,dd, J=2.0, 4.9 Hz), 7.59(2H, s), 7.85(1H, d, J=8.5 Hz), 8.01(1H, d,J=9.0 Hz), 8.13(1H, d, J=8.5 Hz), 8.18(1H, s), 8.78(1H, d, J=7.3 Hz).

Production Example 124 Synthesis of2-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-6-(4-dipropylaminobutyl)-naphtalene[Compound No. 125] Example 124-1 Synthesis oft-butyl-[6-4-methoxy-3-butenyl)-naphthalen-2-yloxy]-dimethyl-silane

Methoxymethyltrifluorophosphonium chloride (425 mg) was dissolved inanhydrous THF (10 ml). Then, the solution obtained was added with a 2mol/l lithium diisopropylamide/THF solution (0.619 ml) underice-cooling, followed by stirring at room temperature for 1 hour. Asolution of the compound (296 mg) obtained in Example 121-7 in anhydrousTHF was added in this solution, and the whole was stirred overnight atroom temperature. After completion of the reaction, distilled water wasadded to the solution, and the whole was stirred. The solution wasextracted with chloroform and the extract was washed with saturatedsaline solution. The organic layer was dried with anhydrous sodiumsulfate. The solvent was distilled off and the residue was then purifiedthrough silica gel column chromatography (hexane/ethyl acetate), therebyobtaining the subject compound (264 mg) (geometrical-isomer mixture) asa yellow oily substance.

(E Isomer)

¹H-NMR(500 MHz, CDCl₃): δ=0.12(6H, s), 0.96(9H, s), 2.33(2H, q, J=6.6Hz), 2.79–2.83(2H, m), 3.48(3H, s), 4.78(1H, q, J=6.3 Hz), 4.88(2H, s),6.32(1H, d, J=6.3 Hz), 7.29–7.36(1H, m), 7.38–7.41(1H, m), 7.59(1H, s),7.73–7.74(3H, m).

(Z Isomer)

¹H-NMR(500 MHz, CDCl₃): δ=0.12(6H, s), 0.96(9H, s), 2.48(2H, q, J=6.6Hz), 2.79–2.83(2H, m), 3.56(3H, s), 4.39(1H, q, J=12.5 Hz), 4.88(2H, s),5.88(1H, d, J=12.5 Hz), 7.29–7.36(1H, m), 7.38–7.41(1H, m), 7.62(1H, s),7.73–7.74(3H, m).

Example 124-2 Synthesis of2-hydroxymethyl-6-(4-dipropylaminobutyl)naphthalene

The compound (263 mg) obtained in Example 124-1 was dissolved in THF(2.0 ml) and then added with distilled water (2.0 ml) and acetic acid(2.0 ml), followed by stirring overnight at room temperature. Aftercompletion of the reaction, the solvent was distilled off and theresidue was obtained. Dipropylamine (253 mg) was dissolved in anhydrousmethanol (5.0 ml). Then sodium cyanoborohydride (69.5 mg), acetic acid(3.0 ml), and the residue described above dissolved in anhydrousmethanol were added to the solution, followed by stirring at roomtemperature for 3 days under a nitrogen atmosphere. After completion ofthe reaction, the solvent was distilled off. The residue was dissolvedin chloroform and added with a saturated aqueous sodium bicarbonatesolution, followed by stirring. Then, the solution was subjected toextraction with chloroform. The extract was washed with a saturatedaqueous sodium bicarbonate solution and saturated saline solution. Theorganic layer was dried with anhydrous sodium sulfate. The solvent wasdistilled off and the residue was then purified through silica gelcolumn chromatography (hexane/ethyl acetate), thereby obtaining thesubject compound (70.0 mg) as a yellow oily substance.

MS(FAB, Pos.): m/z=314[M+H]⁺

Example 124-3 Synthesis of2-phthalimidomethyl-6-(4-dipropylaminobutyl)naphthalene

The compound (70.0 mg) obtained in Example 124-2 was added withtriphenylphosphine (76.1 mg) and phthalimide (36.1 mg), and thendissolved in anhydrous THF (1.0 ml). Subsequently, the solution wasadded with a 40% diethyl azodicarboxylate/toluene solution (0.132 ml) inan ice bath and stirred at room temperature for 3 hours under a nitrogenatmosphere. After completion of the reaction, the solvent was distilledoff and the residue was then purified through silica gel columnchromatography (hexane/ethyl acetate), thereby obtaining the subjectcompound (75.0 mg) as a white solid.

MS(FAB, Pos.): m/z=443[M+H]⁺

Example 124-4 Synthesis of2-aminomethyl-6-(4-dipropylaminobutyl)naphthalene

The compound (75.0 mg) obtained in Example 124-3 was dissolved in a 40%methylamine/methanol solution (2.0 ml) and stirred overnight at roomtemperature. After completion of the reaction, the solvent was distilledoff and then the residue was added with a 1 mol/l sodium hydroxideaqueous solution and stirred. The solution was subjected to extractionwith chloroform and the extract was then washed with saturated salinesolution. Subsequently, the organic layer was dried with anhydroussodium sulfate and the solvent was then distilled off, thereby obtainingthe subject compound (67.5 mg) as a colorless oily substance.

MS(FAB, Pos.): m/z=313[M+H]⁺

Example 124-5 Synthesis of2-{[(1H-imidazol-2-ylmethyl)amino]methyl}-6-(4-dipropylaminobutyl)naphthalene

The compound (67.5 mg) obtained in Example 124-4 was dissolved inanhydrous methanol (2.0 ml) and added with trimethyl orthoformate(0.0354 ml) and 2-imidazole carboxaldehyde (20.8 mg), followed bystirring at room temperature for 2 hours under a nitrogen atmosphere.Subsequently, the solution was added with sodium borohydride (12.3 mg)in an ice bath and then stirred at room temperature for 1 hour. Aftercompletion of the reaction, a saturated aqueous ammonium chloridesolution was added to the solution, and the whole was stirred. Thesolution was subjected to extraction with chloroform and the extract wasthen washed with a saturated aqueous sodium bicarbonate solution andsaturated saline solution. The organic layer was dried with anhydroussodium sulfate. The solvent was distilled off and the residue was thenpurified through silica gel column chromatography (chloroform/ethylacetate), thereby obtaining the subject compound (39.0 mg) as a yellowoily substance.

MS(FAB, Pos.): m/z=393[M+H]⁺

Example 124-6 Synthesis of2-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-6-(4-dipropylaminobutyl)-naphthalene[Compound No. 125]

The compound (39.0 mg) obtained in Example 124-5 was dissolved inanhydrous methanol (1.0 ml) and then added with sodium cyanoborohydride(9.40 mg), acetic acid (1.00 ml), and 1-methyl-2-imidazolecarboxaldehyde (12.0 mg), followed by stirring at room temperature for 2days under a nitrogen atmosphere. After completion of the reaction, thesolvent was distilled off and the residue was then dissolved inchloroform. The solution was added with a saturated aqueous sodiumbicarbonate solution and stirred. The solution was subjected toextraction with chloroform and the extract was then washed with asaturated aqueous sodium bicarbonate solution and saturated salinesolution. The organic layer was dried with anhydrous sodium sulfate andthe solvent was then distilled off. The residue was purified throughsilica gel column chromatography (chloroform/ethyl acetate) and treatedwith hydrochloric acid, thereby obtaining hydrochloride (16.7 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=487[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.88(6H, t, J=7.3 Hz), 1.60–1.75(8H, m),2.77(2H, t, J=6.8 Hz), 2.90–2.98(4H, m), 3.05(2H, t, J=5.4 Hz), 3.68(3H,s), 3.82(2H, s), 4.11(2H, s), 4.18(2H, s), 7.39(1H, d, J=8.5 Hz),7.50(2H, d, J=4.4 Hz), 7.56(1H, d, J=8.5 Hz), 7.64(2H, s), 7.67(1H, s),7.74(1H, d, J=8.5 Hz), 7.81(1H, d, J=8.5 Hz), 7.90(1H, s).

Production Example 125 Synthesis of[4-(6-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-1-propyl-1H-benzimidazol-2-yl)-butyl]-dipropylamine[Compound No. 126] Example 125-1 Synthesis of4-amino-3-propylaminobenzoic acid methyl ester

In DMF (40 ml), methyl 3,4-diaminobenzoate (2.01 g) was dissolved andthen the solution was added with potassium carbonate (2.00 g) and1-iodopropane (1.4 ml), followed by stirring at room temperature for 22hours. After completion of the reaction, the solvent was distilled offunder reduced pressure. The residue was dissolved in ethyl acetate andwashed with water, followed by extraction with ethyl acetate. Theorganic layer was washed with saturated saline solution and dried withanhydrous sodium sulfate. After filtration, the solvent was distilledoff under reduced pressure and the residue was then purified throughsilica gel column chromatography (hexane/ethyl acetate), therebyobtaining the subject compound (1.06 g).

MS(FAB, Pos.): m/z=209[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=1.05(3H, t, J=7.3 Hz), 1.71(2H, sext., J=7.3Hz), 3.12(2H, t, J=7.1 Hz), 3.86(3H, s), 6.69(1H, d, J=8.1 Hz), 7.35(1H,s), 7.45(1H, d, J=8.1 Hz).

Example 125-2 Synthesis of 4-(5-t-butoxycarbonylaminopentanoylamino)-3-propylaminobenzoic acid methyl ester

In chloroform (10 ml), 5-t-butoxycarbonylaminovaleric acid (574 mg),WSCI hydrochloride (690 mg), and HOBt (487 mg) were dissolved. Then, theresulting solution was stirred at room temperature for 30 minutes. Thesolution was added with 4-amino-3-propylaminobenzoic acid methyl (503mg) and stirred overnight at room temperature. After completion of thereaction, the solvent was distilled off under reduced pressure and theresidue was then dissolved in chloroform. After having been washed witha saturated aqueous sodium bicarbonate solution, a saturated aqueousammonium chloride solution, and saturated saline solution, the solutionwas dried with anhydrous sodium sulfate. After filtration, the solventwas distilled off under reduced pressure and the residue was thenpurified through silica gel column chromatography (chloroform/ethylacetate), thereby obtaining the subject compound (540 mg) as a colorlessviscous substance.

MS(FAB, Pos.): m/z=408[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=0.97(3H, t, J=7.3 Hz), 1.37(9H, s),1.37–1.46(2H, m), 1.51-1.66(4H, m), 2.37(2H, t, J=7.3 Hz), 2.93(2H, q,J=6.6 Hz), 3.04(2H, q, J=7.1 Hz), 3.81(3H, s), 5.14(1H, br), 6.83(1H,br), 7.16(1H, s), 7.20(1H, d, J=8.1 Hz), 7.45(1H, d, J=8.1 Hz), 9.24(1H,s).

Example 125-3 Synthesis of2-(4-dipropylaminobutyl)-3-propyl-3H-benzimidazole-5-carboxylic acidmethyl ester

The compound (540 mg) obtained in Example 125-2 was dissolved inmethanol (10 ml) and added with a 4 mol/l hydrogen chloride/dioxanesolution (5 ml), followed by stirring at room temperature for 1.5 hours.After completion of the reaction, the solvent was distilled off underreduced pressure and the residue was then dissolved in methanol,followed by neutralization with the addition of an anion-exchange resin(Amberlite IRA-410). The solvent was distilled off and the residue wasthen dissolved in methanol (12 ml). Subsequently, the solution was addedwith acetic acid (0.425 ml) and sodium cyanoborohydride (135 mg),followed by cooling to 0° C. The solution was added with propionaldehyde(0.114 ml) and stirred at room temperature for 1 hour, followed bycooling to 0° C. again. The solution was added with sodiumcyanoborohydride (132 mg) and propionaldehyde (0.115 ml) and thenstirred overnight at room temperature. After completion of the reaction,the solvent was distilled off under reduced pressure and then theresidue was dissolved in chloroform. The solution was washed with a 1mol/l sodium hydroxide aqueous solution and then subjected to extractionwith chloroform. The organic layer was washed with saturated salinesolution and dried with anhydrous sodium sulfate. After filtration, thesolvent was distilled off under reduced pressure and the residue wasthen purified through silica gel column chromatography(chloroform/methanol), thereby obtaining the subject compound (361 mg)as a colorless viscous substance.

MS(FAB, Pos.): m/z=374[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=0.88(6H, t, J=7.3 Hz), 1.00(3H, t, J=7.3 Hz),1.49(4H, q, J=7.5 Hz), 1.74–1.82(4H, m), 1.87(2H, sext., J=7.6 Hz),1.91–2.09(4H, m), 2.93–3.01(4H, m), 3.00(2H, t, J=7.1 Hz), 3.09(2H, t,J=7.6 Hz), 3.96(3H, s), 4.15(2H, t, J=7.6 Hz), 7.66(1H, d, J=8.5 Hz),7.96(1H, d, J=8.5 Hz), 8.08(1H, s).

Example 125-4 Synthesis of[2-(4-dipropylaminobutyl)-3-propyl-3H-benzimidazol-5-yl]methanol

Lithium aluminum hydride (138 mg) was suspended in THF (7 ml) and thencooled to 0° C. After that, a solution of the compound (361 mg) obtainedin Example 125-3 in THF (7 ml) was dropped in the suspension, followedby stirring at 0° C. for 1 hour. After completion of the reaction,sodium sulfate decahydrate was continuously added to the solution untilbubbling was stopped, and a 1 mol/l sodium hydroxide aqueous solutionwas then added to the mixture until a white precipitate was generated.Solid matter was separated through filtration and the solvent was thendistilled off from the filtrate under reduced pressure. The residue wasdried under vacuum, thereby obtaining the subject compound (302 mg) as apale-yellow viscous substance.

MS(FAB, Pos.): m/z=346[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.82(6H, t, J=7.3 Hz), 0.89(3H, t, J=7.3Hz), 1.37(4H, sext., J=7.3 Hz), 1.50(2H, quint., J=7.3 Hz),1.70–1.81(4H, m), 2.29(4H, t, J=7.3 Hz), 2.39(2H, t, J=7.1 Hz), 2.84(2H,t, J=7.6 Hz), 4.11(2H, t, J=7.3 Hz), 4.59(2H, d, J=5.2 Hz), 5.16(1H, t,J=5.5 Hz), 7.09(1H, d, J=8.2 Hz), 7.42(1H, s), 7.45(1H, d, J=8.2 Hz).

Example 125-5 Synthesis of2-[2-(4-dipropylaminobutyl)-3-propyl-3H-benzimidazol-5-ylmethyl]isoindole-1,3-dione

The compound (302 mg) obtained in Example 125-4 was dissolved in toluene(6.0 ml) and added with triphenylphosphine (275 mg) and phthalimide (193mg), followed by cooling to 0° C. In this solution, a 40% diethylazodicarboxylate/toluene solution (452 mg) was dropped. After that, thesolution was stirred overnight at room temperature. After completion ofthe reaction, the solvent was distilled off under reduced pressure. Theresidue was dissolved in chloroform and washed with water. Then, thesolution was subjected to extraction with chloroform and the extract wasthen washed with saturated saline solution. The organic layer was driedwith anhydrous sodium sulfate. After filtration, the solvent wasdistilled off under reduced pressure and the residue was then purifiedthrough silica gel column chromatography (chloroform/methanol), therebyobtaining the subject compound (174 mg) as a pale-yellow solid.

MS(FAB, Pos.): m/z=475[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.79–0.83(6H, m), 0.86(3H, t, J=7.3 Hz),1.31–1.40(4H, m), 1.46–1.51(2H, m), 1.63–1.80(4H, m), 2.29(4H, br),2.39(2H, br), 2.83(2H, t, J=7.6 Hz), 4.12(2H, t, J=7.3 Hz), 4.87(2H, s),7.08(1H, d, J=8.3 Hz), 7.46–7.48(2H, m), 7.83–7.89(2H, m), 7.90–7.93(2H,m).

Example 125-6 Synthesis of[4-(6-aminomethyl-1-propyl-1H-benzimidazol-2-yl)butyl]dipropylamine

The compound (173 mg) obtained in Example 125-5 was dissolved in a 40%methylamine/methanol solution (1.8 ml) and stirred at room temperaturefor 17 hours. After completion of the reaction, the solvent wasdistilled off under reduced pressure and the residue was then purifiedthrough silica gel column chromatography (chloroform/ethyl acetate),thereby obtaining the subject compound (130 mg) as a pale-yellow viscoussubstance.

MS(FAB, Pos.): m/z=345[M+H]⁺

Example 125-7 Synthesis of[4-(6-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}-1-propyl-1H-benzimidazol-2-yl)butyl]dipropylamine

The compound (130 mg) obtained in Example 125-6 was dissolved inmethanol (3.0 ml) and added with trimethyl orthoformate (0.130 ml) and2-imidazole carboxaldehyde (37.3 mg), followed by stirring for 1 hour.Then, the solution was cooled to 0° C. The solution was added withsodium borohydride (21.5 mg) and stirred at room temperature for 3hours. After completion of the reaction, the solvent was distilled offunder reduced pressure and the residue was then dissolved in chloroform.The solution was washed with a 1 mol/l sodium hydroxide aqueous solutionand then subjected to extraction with chloroform. The organic layer waswashed with saturated saline solution and then dried with anhydroussodium sulfate. After filtration, the solvent was distilled off underreduced pressure. Then, the residue was purified through silica gelcolumn chromatography (chloroform/methanol) and treated withhydrochloric acid, thereby obtaining hydrochloride (16.4 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=505[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.91(6H, t, J=7.3 Hz), 0.99(3H, t, J=7.3Hz), 1.66–1.71(4H, m), 1.78–1.82(4H, m), 1.83–1.96(2H, m), 2.97–3.00(4H,m), 3.08–3.16(2H, m), 3.25(2H, t, J=7.2 Hz), 3.87(2H, s), 4.16(4H, s),4.54(2H, t, J=7.7 Hz), 7.52–7.55(1H, m), 7.61(3H, s), 7.64–7.70(1H, m),8.43(1H, s), 10.31(1H, br)

Production Example 126 Synthesis of[4-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1-propyl-1H-benzimidazol-2-yl)-butyl]-dipropylamine[Compound No. 127] Example 126-1 Synthesis of[4-(6-{[(1H-imidazol-2-ylmethyl)amino]methyl}-1-propyl-1H-benzimidazol-2-yl)butyl]dipropylamine

The compound (130 mg) obtained in Example 125-6 was dissolved inmethanol (3.0 ml) and added with trimethyl orthoformate (0.130 ml) and2-imidazole carboxaldehyde (37.3 mg), followed by stirring for 1 hour.Then, the solution was cooled to 0° C. The solution was added withsodium borohydride (21.5 mg) and stirred at room temperature for 3hours. After completion of the reaction, the solvent was distilled offunder reduced pressure and the residue was then dissolved in chloroform.The solution was washed with a 1 mol/l sodium hydroxide aqueous solutionand then subjected to extraction with chloroform. The organic layer waswashed with saturated saline solution and then dried with anhydroussodium sulfate. After filtration, the solvent was distilled off underreduced pressure. Then, the residue was purified through silica gelcolumn chromatography (chloroform/methanol), thereby obtaining thesubject compound (64.0 mg) as a pale-yellow viscous substance.

Example 126-2 Synthesis of[4-(6-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-1-propyl-1H-benzimidazol-2-yl)-butyl]-dipropylamine[Compound No. 126]

The compound (64.0 mg) obtained in Example 126-1 was dissolved inmethanol (1.3 ml) and added with acetic acid (0.065 ml) and1-methyl-2-imidazole carboxaldehyde (16.6 mg), followed by cooling to 0°C. Then, the solution was added with sodium cyanoborohydride (14.2 mg)and stirred at room temperature for 2 days. After completion of thereaction, the solvent was distilled off under reduced pressure and theresidue was then dissolved in chloroform. After washing with a 1 mol/lsodium hydroxide aqueous solution, the solution was subjected toextraction with chloroform. The organic layer was washed with saturatedsaline solution and dried with anhydrous sodium sulfate. Afterfiltration, the solvent was distilled off under reduced pressure.Subsequently, the residue was purified through silica gel columnchromatography (chloroform/methanol) and treated with hydrochloric acid,thereby obtaining hydrochloride (30.0 mg) of the subject compound as awhite solid.

MS(FAB, Pos.): m/z=519[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.91(6H, t, J=7.3 Hz), 0.99(3H, t, J=7.3Hz), 1.66–1.74(4H, m), 1.78–1.84(4H, m), 1.93(2H, t, J=7.3 Hz),2.94–3.00(4H, m), 3.13(2H, br), 3.26(2H, t, J=7.3 Hz), 3.73(3H, s),3.90(2H, s), 4.13(2H, s), 4.21(2H, s), 4.53(2H, t, J=7.6 Hz),7.53–7.55(3H, m), 7.63(2H, s), 7.70(1H, d, J=8.2 Hz), 8.41(1H, s),10.48(1H, br).

Production Example 127 Synthesis of[4-(5-{[(imidazol-2-ylmethyl)-(1-methylimidazol-2-ylmethyl)-amino]-methyl}-1-methoxy-indan-2-yl)-butyl]-dipropylamine[Compound No. 128] Example 127-1 Synthesis of4-(t-butyldiphenylsilyloxyl)-butan-1-ol

Commercially available 1,4-butanediol (400 g) was dissolved in DMF (120ml), added with imidazole (3.02 g) and t-butyldiphenylchlorosilane (12.2g), and stirred at room temperature for 15 hours. The reaction solutionwas concentrated under reduced pressure and then added with a saturatedaqueous ammonium chloride solution, followed by separation/extractionwith chloroform. The organic layer was washed with saturated salinesolution and dried with anhydrous sodium sulfate, followed byconcentration under reduced pressure. The residue was purified throughsilica gel column chromatography (hexane/ethyl acetate), therebyobtaining the subject compound (6.56 g) as a transparent and colorlessoily substance.

¹H-NMR(500 Mz, CDCl₃): δ=1.05(9H, s), 1.63–1.71(4H, m), 2.05(1H, t,J=5.1 Hz), 3.66(2H, dt, J=5.1, 5.9 Hz), 3.70(2H, t, J=5.9 Hz),7.37–7.45(6H, m), 7.67(4H, d, J=8.5 Hz).

Example 127-2 Synthesis of 4-(t-butyldiphenylsilyloxy)butylaldehyde

The compound (6.56 g) obtained in Example 127-1 was dissolved indichloromethane (262 ml) and then added with Molecular Sieves 4A (32.8g), N-methylmorpholin-N-oxide (7.02 g), and tetrapropylammoniumperruthenate (702 mg), followed by stirring at room temperature for 2hours. The reaction solution was filtrated through Celite and thefiltrate was then concentrated under reduced pressure. The residue waspurified through silica gel column chromatography (hexane/ethyl acetate)and the subject compound (3.86 g) was then obtained as a colorless oilysubstance.

Example 127-3 Synthesis of5-bromo-2-[4-(t-butyldiphenylsilyloxy)butyliden]indan-1-one

Commercially available 5-bromoindanone (2.50 g) was dissolved in THF(75.0 ml). The solution was added with a 1 mol/l lithiumbistrimethylsilyl amide/hexane solution (11.8 ml) while being stirred at−78° C., followed by stirring for 30 minutes. Subsequently, a solutionof the compound (3.86 g) obtained in Example 127-2 in THF (15.0 ml) wasgradually added to the solution, and further the whole was stirred for 3hours. The reaction solution was added with a saturated aqueous ammoniumchloride solution and then subjected to separation/extraction withchloroform. The organic layer was dried with anhydrous sodium sulfateand concentrated under reduced pressure. The residue was dissolved inDMF (75.0 ml) and then added with methanesulfonyl chloride (2.71 g) andtriethylamine (2.63 g) while being stirred under ice-cooling, followedby stirring at room temperature for 1 hour. Subsequently, the solutionwas added with 1,8-diazo-bicyclo[5,4,0]undec-7-en (3.97 g) and stirredat 70° C. for 1 hour. The reaction solution was concentrated underreduced pressure and the residue was then added with a saturated aqueousammonium chloride solution, followed by separation/extraction withchloroform. The organic layer was dried with anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purifiedthrough silica gel column chromatography (hexane/diethyl ether), therebyobtaining the subject compound (4.56 g) as a brown oily substance.

¹H-NMR(500 Mz, CDCl₃): δ=1.06(9H, s), 1.77(2H, quint., J=6.1 Hz),2.42(2H, dt, J=6.1, 7.6 Hz), 3.62(2H, s), 3.71(2H, t, J=7.1 Hz),6.88(1H, t, J=7.6 Hz), 7.34–7.44(7H, m), 7.54(1H, d, J=8.3 Hz), 7.64(4H,d, J=8.1 Hz), 7.71(1H, d, J=8.3 Hz).

Example 127-4 Synthesis of5-bromo-2-[4-(t-butyldiphenylsilyloxy)butyl]indan-1-one

The compound (4.56 g) obtained in Example 127-3 was dissolved in THF(136.8 ml). Then, the solution was added with a 1 mol/l K-Selectride®(manufactured by Aldrich Corporation)-THF solution (8.76 ml) while beingstirred at −78° C., followed by stirring at the same temperature for 1hour. The reaction solution was added with a saturated aqueous ammoniumchloride solution and then subjected to separation/extraction withchloroform. The organic layer was washed with saturated saline solutionand dried with anhydrous sodium sulfate, followed by concentration underreduced pressure. The residue was purified through silica gel columnchromatography (hexane/diethyl ether), thereby obtaining the subjectcompound (2.03 g) as a yellow oily substance.

Example 127-5 Synthesis of5-bromo-2-[4-(t-butyldiphenylsilyloxy)butyl]indan-1-ol

The compound (2.03 g) obtained in Example 127-4 was dissolved inmethanol (60.9 ml) and THF (30.5 ml) and, under ice-cooling, added withsodium borohydride (0.442 g), followed by stirring at room temperaturefor 2 hours. The reaction solution was added with a saturated aqueousammonium chloride solution and then subjected to separation/extractionwith chloroform. The organic layer was dried with anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified through silica gel column chromatography (hexane/ethylacetate), thereby obtaining the subject compound (1.54 g) as a yellowoily substance.

Example 127-6 Synthesis of[4-(5-bromo-1-methoxymethoxy-1-indan-2-yl)-butoxy]-t-butyldiphenylsilane

The compound (1.54 g) obtained in Example 127-5 was dissolved in DMF(46.2 ml) and, while being stirred under ice-cooling, added with 60%sodium hydride (235 mg) and chloromethylmethylether (592 mg), followedby stirring at room temperature for 24 hours. The reaction solution wasadded with water and subjected to separation/extraction with chloroform.After having been washed with saturated saline solution, the organiclayer was dried with anhydrous sodium sulfate, concentrated underreduced pressure, and dried under vacuum. The residue was purifiedthrough silica gel column chromatography (hexane/ethyl acetate), therebyobtaining the subject compound (1.64 g) as a yellow oily substance.

Example 127-7 Synthesis of3-(5-bromo-1-methoxymethoxy-indan-2-yl)butylaldehyde

The compound (1.64 g) obtained in Example 127-6 was dissolved in THF(49.2 ml), added with a 1 mol/l TBAF/THF solution (4.69 ml), and stirredat room temperature for 3 hours. The reaction solution was concentratedunder reduced pressure and added with water, followed byseparation/extraction with chloroform. After having been washed withsaturated saline solution, the organic layer was dried with anhydroussodium sulfate, concentrated under reduced pressure, and dried undervacuum. The residue was dissolved in dichloromethane (41.2 ml) again.Then, the solution was added with Molecular Sieves 4A (5.15 g),N-methylmorpholine-N-oxide (1.10 g), tetrapropylammonium perruthenate(109 mg), followed by stirring at room temperature for 1 hour. Thereaction solution was filtrated through Celite and the filtrate was thenconcentrated under reduced pressure. The residue was purified throughsilica gel column chromatography (hexane/ethyl acetate), therebyobtaining the subject compound (0.574 g) as a pale-yellow oilysubstance.

Example 127-8 Synthesis of5-bromo-2-(3-dipropylaminobutyl)-1-methoxy]methoxy-indane

The compound (574.0 mg) obtained in Example 127-7 was dissolved in1,2-dichloroethane (28.7 ml), while being stirred at room temperature,added with di-n-propylamine (266.3 mg) and sodium triacetoxy borohydride(743.6 mg), followed by stirring for 20 hours. The reaction solution wasadded with a 1 mol/l sodium hydroxide aqueous solution and subjected toseparation/extraction with chloroform. Then, the organic solvent waswashed with saturated saline solution and dried with anhydrous sodiumsulfate, followed by concentration under reduced pressure. The residuewas purified through silica gel column chromatography(chloroform/methanol), thereby obtaining the subject compound (552.4 mg)as a yellow oily substance.

Example 127-9 Synthesis of5-cyano-2-(3-dipropylaminobutyl)-1-methoxymethoxy-indane

The compound (552.4 mg) obtained in Example 127-8 was dissolved in DMF(1.67 ml) and added with zinc cyanide (94.3 mg) and tetrakistriphenylphosphine palladium (61.8 mg), followed by stirring at 80° C. for 48hours. The reaction solution was added with chloroform and washed with a7% aqueous ammonium solution and saturated saline solution. The solutionwas dried with anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified through silica gel columnchromatography (chloroform/methanol), thereby obtaining the subjectcompound (436.8 mg) as a yellow oily substance.

Example 127-10 Synthesis of5-aminomethyl-2-(3-dipropylaminobutyl)-1-methoxymethoxy-indane

The compound (436.8 mg) obtained in Example 127-9 was dissolved in THF(21.8 ml) and added with lithium aluminum hydride (138.7 mg), followedby stirring at room temperature for 24 hours. The reaction solution wasadded with ethyl acetate, methanol, and a 10% aqueous potassium sodiumtartrate solution, and stirred for 1 hour, followed byseparation/extraction with chloroform. The extract was washed withsaturated saline solution and dried with anhydrous sodium sulfate,followed by concentration under reduced pressure. The residue waspurified through silica gel column chromatography (chloroform/ethylacetate), thereby obtaining the subject compound (189.7 mg) as a yellowoily substance.

Example 127-11 Synthesis of2-[2-(4-dipropylaminobutyl)-1-methoxymethoxy-indan-5-ylmethyl]-isoindole-1,3-dione

The compound (189.7 mg) obtained in Example 127-10 was dissolved in DMF(5.69 ml) and added with potassium carbonate (108.5 mg) andcarbethoxyphthalimide (172.0 mg), followed by stirring at roomtemperature for 3 hours. The reaction solution was added with water.Then, the solution was subjected to separation/extraction withchloroform, dried with anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified through silica gel columnchromatography (chloroform/methanol), thereby obtaining the subjectcompound (253.9 mg) as a yellow oily substance.

MS(FAB, Pos.): m/z=493[M+H]⁺

Example 127-12 Synthesis of2-[2-(4-dipropylamino-butyl)-1-methoxy-indan-5-ylmethyl]-isoindole-1,3-dione

The compound (253.9 mg) obtained in Example 127-11 was dissolved inmethanol (10.2 ml), added with a 10% hydrogen chloride/methanol solution(5.08 ml), and stirred for 16 hours at room temperature. Then, thereaction solution was concentrated under reduced pressure and driedunder vacuum. The residue was purified through silica gel columnchromatography (hexane/ethyl acetate), thereby obtaining the subjectcompound (95.7 mg) as a yellow oily substance.

MS(FAB, Pos.): m/z=463[M+H]⁺

Example 127-13 Synthesis of[4-(5-aminomethyl-1-methoxyindan-2-yl)-butyl]-dipropylamine

The compound (95.7 mg) obtained in Example 127-12 was dissolved inmethanol (4.79 ml) and added with hydrazine monohydrate (0.0957 ml),followed by thermal reflux for 1 hour. The reaction solution wasconcentrated under reduced pressure. Then, the residue was added withwater and subjected to separation/extraction with chloroform, dried withanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified through silica gel column chromatography(chloroform/ethyl acetate), thereby obtaining the subject compound (45.0mg) as a yellow oily substance.

MS(FAB, Pos.): m/z=333[M+H]⁺

Example 127-14 Synthesis of[4-(5-{[(imidazol-2-ylmethyl)-amino]-methyl}-1-methoxyindan-2-yl)-butyl]-dipropylamine

The compound (45.0 mg) obtained in Example 127-13 was dissolved inmethanol (2.25 ml) and added with 2-imidazole carboxaldehyde (19.5 mg)and trimethyl orthoformate (43.1 mg), followed by stirring at roomtemperature for 1 hour. Under ice-cooling, sodium borohydride (15.4 mg)was added to the solution, and the whole was stirred at room temperaturefor 30 minutes. The reaction solution was added with water and thensubjected to separation/extraction with chloroform. The extract waswashed with saturated saline solution, dried with anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified throughsilica gel column chromatography (chloroform/methanol), therebyobtaining the subject compound (54.8 mg) as a yellow oily substance.

MS(FAB, Pos.): m/z=412[M+H]⁺

Example 127-15 Synthesis of[4-(5-{[(imidazol-2-ylmethyl)-(1-methylimidazol-2-ylmethyl)-amino]-methyl}-1-methoxy-indan-2-yl)-butyl]-dipropylamine[Compound No. 128]

The compound (54.8 mg) obtained in Example 127-14 was dissolved inmethanol (2.74 ml) and added with 1-methyl-2-imidazole carboxaldehyde(21.9 mg) and sodium cyanoborohydride (16.7 mg). Then, the solution wasadjusted to pH 4 with acetic acid and stirred at room temperature for 3hours. The reaction solution was concentrated under reduced pressure andadded with saturated saline solution. The solution was subjected toseparation/extraction with chloroform. The extract was dried withanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified through silica gel column chromatography(chloroform/methanol) and treated with hydrochloric acid, therebyobtaining hydrochloride (35.9 mg) of the subject compound as a whitesolid.

MS(FAB, Pos.): m/z=507[M+H]⁺

Production Example 128 Synthesis of[4-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1-propyl-1H-benzimidazol-2-yl)-butyl]-dipropylamine[Compound No. 129] Example 128-1 Synthesis of 3-nitro-4-propylaminobenzonitrile

In DMF (15 ml), 3-nitro-4-aminobenzonitrile (500 mg) was dissolved, andthe solution was added with sodium hydride (135 mg), followed bystirring at room temperature for 9 hours. The solution was added with1-iodopropane (328 ml) and stirred overnight at room temperature. Aftercompletion of the reaction, the solvent was distilled off under reducedpressure and the residue was then dissolved in chloroform. The solutionwas washed with water and then subjected to extraction with chloroform.The organic layer was washed with saturated saline solution and driedwith anhydrous sodium sulfate. After filtration, the solvent wasdistilled off under reduced pressure and the residue was then purifiedthrough silica gel column chromatography (chloroform), thereby obtainingthe subject compound (362 mg) as a white solid.

MS(FAB, Pos.): m/z=206[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=1.08(3H, t, J=7.6 Hz), 1.79(2H, sext., J=7.3Hz), 3.33(2H, q, J=7.1 Hz), 6.91(1H, d, J=9.0 Hz), 7.60(1H, d, J=9.0Hz), 8.43(1H, br), 8.52(1H, s).

Example 128-2 Synthesis of 3-amino-4-propylaminobenzonitrile

In ethanol (10 ml) and THF (1.0 ml), 3-amino-4-propylaminobenzonitrile(360 mg) and tin(II) chloride dihydrate (4.01 g) were dissolved. Then,the solution was heated to 60° C. and a solution (3.0 ml) of sodiumborohydride (50.3 mg) in ethanol was then dropped therein, followed bystirring at 60° C. for 1 hour. After completion of the reaction, waterwas added to the solution, and the whole was neutralized with a 1 mol/lsodium hydroxide aqueous solution. Then, ethanol and THF were distilledoff under reduced pressure. The residue was subjected to extraction withether. The extract was washed with saturated saline solution and driedwith anhydrous sodium sulfate. After filtration, the solvent wasdistilled off under reduced pressure. The residue was purified throughsilica gel column chromatography (chloroform/methanol), therebyobtaining the subject compound (284 mg) as a white solid.

MS(FAB, Pos.): m/z=176[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=1.04(3H, t, J=7.6 Hz), 1.70(2H, sext., J=7.3Hz), 3.13(2H, q, J=7.1 Hz), 6.58(1H, d, J=8.1 Hz), 6.94(1H, s), 7.17(1H,d, J=8.1 Hz).

Example 128-3 Synthesis oft-butyl[4-(5-cyano-2-propylaminophenylcarbamoyl)butyl]carbamate

In chloroform (5.0 ml), 5-t-butoxycarbonylaminovaleric acid (387 mg),WSCI hydrochloride (466 mg), and HOBt (328.3 mg) were dissolved. Then,the solution was stirred at room temperature for 1 hour. A solution (3.0ml) of 3-amino-4-propylaminobenzonitrile (283 mg) in chloroform wasdropped in this solution. Then, the solution was stirred overnight atroom temperature. After completion of the reaction, the solvent wasdistilled off under reduced pressure. The residue was dissolved inchloroform and then washed with a saturated aqueous sodium bicarbonatesolution, a saturated aqueous ammonium chloride solution, and saturatedsaline solution, followed by drying with anhydrous sodium sulfate. Afterfiltration, the solvent was distilled off under reduced pressure and theresidue was then purified through silica gel column chromatography(chloroform/ethyl acetate), thereby obtaining the subject compound as acolorless viscous substance.

MS(FAB, Pos.): m/z=375[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.93(3H, t, J=7.3 Hz), 1.34–1.46(2H, m),1.38(9H, s), 1.57(2H, sext., J=7.3 Hz), 2.34(2H, t, J=7.3 Hz), 2.93(2H,q, J=6.6 Hz), 3.10(2H, q, J=7.3 Hz), 5.86(1H, t, J=5.2 Hz), 6.69(1H, d,J=8.5 Hz), 6.83(1H, t, J=5.6 Hz), 7.41(1H, d, J=8.5 Hz). 7.51(1H, s),9.13(1H, s).

Example 128-4 Synthesis of2-(dipropylaminobutyl)-1-propyl-1H-benzimidazole-5-carbonitrile

The compound obtained in Example 128-3 was dissolved in methanol (3.0ml) and added with a 4 mol/l hydrogen chloride/dioxane solution (3.0ml), followed by stirring at room temperature for 14 hours. Aftercompletion of the reaction, the solvent was distilled off under reducedpressure and the residue was dried under vacuum. The dried product wasdissolved in methanol and neutralized with an anion-exchange resin(Amberlite IRA-410), followed by distilling the solvent off. The residuewas dissolved in methanol (8.0 ml) again. Then, the solution was addedwith acetic acid (0.268 ml) and propionaldehyde (0.225 ml), followed bycooling to 0° C. The solution was added with sodium cyanoborohydride(209.0 mg) and stirred overnight at room temperature. After completionof the reaction, the solvent was distilled off under reduced pressure.The residue was dissolved in chloroform and washed with a 1 mol/l sodiumhydroxide aqueous solution, followed by extraction with chloroform. Theorganic layer was washed with saturated saline solution and then driedwith anhydrous sodium sulfate. After filtration, the solvent wasdistilled off under reduced pressure and the residue was then purifiedthrough silica gel column chromatography (chloroform/methanol), therebyobtaining the subject compound (97.1 mg) as a colorless viscoussubstance.

MS(FAB, Pos.): m/z=341[M+H]⁺

Example 128-5 Synthesis of[4-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1-propyl-1H-benzimidazol-2-yl)-butyl]-dipropylamine[Compound No. 129]

Lithium aluminum hydride (40.6 mg) was suspended in THF (3.0 ml) andcooled to 0° C. A solution (2.0 ml) of the compound (97.1 mg) obtainedin Example 128-4 in THF was dropped in this suspension. Then, thesuspension was stirred at 0° C. for 1 hour. Furthermore, lithiumaluminum hydride (41.0 mg) was added to the suspension, and the wholewas stirred for 2 days. After completion of the reaction, sodium sulfatedecahydrate was added to the suspension until bubbling was stopped.Subsequently, a 1 mol/l sodium hydroxide aqueous solution was added tothe suspension until a white precipitate was generated. Solid matter wasseparated through filtration and the solvent was then distilled off fromthe filtrate under reduced pressure. The residue was dried under vacuum,dissolved in methanol (2.0 ml), and added with trimethyl orthoformate(0.11 ml) and 2-imidazole carboxaldehyde (31.0 mg). Then, the solutionwas stirred for 1 hour and then cooled to 0° C. The solution was addedwith sodium borohydride (19.7 mg) and stirred at room temperature for 1hour. After completion of the reaction, the solvent was distilled offunder reduced pressure and the residue was then dissolved in 1 mol/lhydrochloric acid and the aqueous layer was then washed with chloroform.The resultant was added with a 1 mol/l sodium hydroxide aqueous solutionand then extracted with chloroform. The organic layer was washed withsaturated saline solution and dried with anhydrous sodium sulfate,followed by distilling the solvent off. The residue was dissolved inmethanol (2.0 ml) and added with acetic acid (0.10 ml) and1-methyl-2-imidazole carboxaldehyde (35.1 mg), followed by cooling to 0°C. The solution was added with sodium cyanoborohydride (31.7 mg) andstirred at room temperature for 14 hours. After completion of thereaction, the solvent was distilled off under reduced pressure. Theresidue was dissolved in chloroform and washed with a 1 mol/l sodiumhydroxide aqueous solution, followed by extraction with chloroform. Theorganic layer was washed with saturate saline solution and dried withanhydrous sodium sulfate. After filtration, the solvent was distilledoff under reduced pressure. Then, the residue was purified throughsilica gel column chromatography (chloroform/methanol) and treated withhydrochloric acid, thereby obtaining hydrochloride (89.4 mg) of thesubject compound as a white solid.

MS(FAB, Pos.): m/z=519[M+H]⁺

¹H-NMR(500 MHz, DMSO-d₆): δ=0.89–0.95(9H, m), 1.67–1.94(10H, m),2.96–3.00(4H, m), 3.12–3.13(2H, m), 3.26(2H, t, J=7.3 Hz), 3.72(3H, s),3.91(2H, s), 4.13(2H, s), 4.21(2H, s), 4.41(2H, t, J=7.3 Hz), 7.49(1H,s), 7.52(1H, s), 7.64(2H, s), 7.72(1H, d, J=8.5 Hz), 7.82(1H, s),7.90(1H, d, J=8.5 Hz), 10.61 (1H, s).

Production Example 129 Synthesis of2-(4-di-n-propylamino-butyl)-5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-isoindole-1,3-dione[Compound No. 130] Example 129-1 Synthesis of 4-methylphthalic aciddimethyl ester

In methanol (60 ml), 4-methylphthalic acid (3.00 g) was dissolved. Then,WSCI hydrochloride (9.62 g) and 4-dimethylaminopyridine (3.07 g) wereadded to the solution, and the whole was stirred at room temperature for3.5 hours. The reaction solution was added with water and then subjectedto extraction with chloroform. The organic layer was washed with water,1 mol/l hydrochloric acid, and saturated saline solution, and then driedwith anhydrous sodium sulfate. The solvent was distilled off and theresidue was purified through silica gel column chromatography(hexane/ethyl acetate), thereby obtaining the subject compound (2.54 g)as a colorless oily substance.

MS(FAB, Pos.): m/z=209[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=2.42(3H, s), 3.89(3H, s), 3.91(3H, s),7.33(1H, dd, J=1.7, 8.6 Hz), 7.47(1H, d, J=1.2 Hz), 7.68(1H, d, J=7.8Hz).

Example 129-2 Synthesis of4-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-phthalic acid dimethylester

The compound (202 mg) obtained in Example 129-1 was dissolved in carbontetrachloride (7.1 ml) and added with N-bromosuccinimide (205 mg) andazobisisobutyronitrile (15.8 mg), followed by thermal reflux for 20hours. The solution was further added with carbon tetrachloride (7.0 ml)and N-bromosuccinimide (51.3 mg), followed by thermal reflux for 4hours. After having been stood to cool, the solution was added withwater and then subjected to extraction with chloroform. The organiclayer was washed with water and saturated saline solution and then driedwith anhydrous sodium sulfate. The solvent was distilled off and theresidue was then dissolved in DMF (5.8 ml). The solution was added withpotassium phthalimide (359 mg) and stirred at room temperature for 16hours. The residue obtained by distilling the solvent off was purifiedthrough silica gel column chromatography (hexane/ethyl acetate), therebyobtaining the subject compound (226 mg) as a white solid.

MS(FAB, Pos.): m/z=354[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=3.88(3H, s), 3.90(3H, s), 4.89(2H, s),7.60(1H, dd, J=1.8, 8.1 Hz), 7.71(1H, d, J=7.9 Hz), 7.74(2H, dd, J=2.9,5.5 Hz), 7.75(1H, m), 7.87(2H, dd, J=2.9, 5.5 Hz).

Example 129-3 Synthesis of 4-(t-butoxycarbonylamino-methyl)-phthalicacid dimethyl ester

The compound (909 mg) obtained in Example 129-2 was suspended inmethanol (22 ml). Hydrazine monohydrate (0.13 ml) was dropped in thissuspension. Then, the solution was subjected to thermal reflux for 4hours. After completion of the reaction, the solvent was distilled offunder reduced pressure and then the residue was subjected to extractionwith chloroform. The organic layer was washed with water and then washedwith saturated saline solution, followed by drying with anhydrous sodiumsulfate. The residue obtained by distilling the solvent off wasdissolved in DMF (15 ml) and added with triethylamine (0.54 ml) anddi-t-butyl dicarbonate (851 mg), followed by stirring at roomtemperature for 15 hours. After the solvent had been distilled off, theresidue was subjected to extraction with chloroform. The organic layerwas washed with water and saturated saline solution and then dried withanhydrous sodium sulfate. The residue obtained by distilling the solventoff was purified through silica gel column chromatography (hexane/ethylacetate), thereby obtaining the subject compound (779 mg) as a yellowoily substance.

MS(FAB, Pos.): m/z=324[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=1.47(9H, s), 3.90(3H, s), 3.91(3H, s),4.38(2H, d, J=6.1 Hz), 4.94(1H, br), 7.46(1H, d, J=8.5 Hz), 7.61(1H, d,J=1.5 Hz), 7.72(1H, d, J=7.8 Hz).

Example 129-4 Synthesis of 4-(t-butoxycarbonylamino-methyl)-phthalicacid

The compound (76.4 mg) obtained in Example 129-3 was dissolved inmethanol (4.5 ml). A 1 mol/l sodium hydroxide aqueous solution (2.3 ml)was dropped in this solution. Then, the solution was stirred at roomtemperature for 2 hours and then neutralized with the addition of 1mol/l hydrochloric acid (2.3 ml). The residue obtained by distilling thesolvent off was purified through silica gel column chromatography(chloroform/methanol), thereby obtaining the subject compound (65.3 mg)as a pale-yellow oily substance.

MS(FAB, Pos.): m/z=296[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=1.45(9H, s), 4.30(2H, s), 7.45(1H, d, J=7.6Hz), 7.80(1H, s), 7.88(1H, d, J=8.1 Hz).

Example 129-5 Synthesis of[2-(4-di-N-propylamino-butyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-carbamicacid t-butyl ester

The compound (209.4 mg) obtained in Example 129-4 was dissolved inxylene (8.0 ml) and added with the compound (150 mg) obtained in Example1-2, followed by thermal reflux for 24 hours. The solution was addedwith water and then extracted with chloroform. The organic layer waswashed with water and saturated saline solution, followed by drying withanhydrous sodium sulfate. The solvent was distilled off and the residuewas then purified through silica gel column chromatography (hexane/ethylacetate), thereby obtaining the subject compound (92.3 mg) as a yellowsolid.

MS(FAB, Pos.): m/z=432[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=0.85(6H, t, J=7.4 Hz), 1.40–1.50(6H, m),1.47(9H, s), 1.64–1.70(2H, m), 2.34(4H, t, J=7.4 Hz), 2.42(2H, t, J=7.5Hz), 3.69(2H, t, J=7.3Hz), 4.45(2H, d, J=6.1 Hz), 5.04(1H, br), 7.62(1H,d, J=7.5 Hz), 7.76(1H, d, J=0.8 Hz), 7.79(1H, d, J=7.6 Hz).

Example 129-6 Synthesis of2-(4-di-N-propylamino-butyl)-5-{[(1H-imidazol-2-ylmethyl)-amino]-methyl}-isoindole-1,3-dione

The compound (128 mg) obtained in Example 129-5 was dissolved inmethanol (1.5 ml). A 4 mol/l hydrogen chloride/dioxane solution (1.5 ml)was dropped in this solution. Then, the solution was stirred at roomtemperature for 1 hour. The residue obtained by distilling the solventoff was dissolved in methanol and added with an anion-exchange resin(Amberlite IRA-410), followed by adjusting the solution to pH 7–8. Theresin was separated through filtration and the solvent was distilled offfrom the filtrate. Subsequently, the residue was dissolved in methanol(3.0 ml) and added with trimethyl orthoformate (0.1 ml) and 2-imidazolecarboxaldehyde (43.2 mg), followed by stirring at room temperature for 2hours. The solution was added with sodium borohydride (17.0 mg) andstirred for 4 hours. Then, the solution was added with water andextracted with chloroform. The organic layer was washed with water andsaturated saline solution and dried with anhydrous sodium sulfate. Theresidue obtained by distilling the solvent off was purified throughsilica gel column chromatography (chloroform/methanol), therebyobtaining the subject compound (25.8 mg) as a white solid.

MS(FAB, Pos.): m/z=412[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=0.79(6H, t, J=7.4 Hz), 1.30–1.38(6H, m),1.57–1.62(2H, m), 2.25(4H, t, J=7.2 Hz), 2.33(2H, t, J=6.9 Hz), 3.57(2H,t, J=6.9 Hz), 3.68(2H, s), 3.84(2H, s), 6.79(1H, s), 7.02(1H, s),7.79(1H, d, J=7.1 Hz), 7.80(1H, d, J=7.4 Hz), 7.88(1H, s), 11.81(1H,br).

Example 129-7 Synthesis of2-(4-di-n-propylamino-butyl)-5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-isoindole-1,3-dione[Compound No. 130]

The compound (24.9 mg) obtained in Example 129-6 was dissolved inmethanol (2.0 ml) and added with 1-methyl-2-imidazole carboxaldehyde(7.9 mg) and sodium cyanoborohydride (7.5 mg). Then, the solution wasadjusted to pH 4 with acetic acid and stirred at room temperature for 16hours. The solution was further added with 1-methyl-2-imidazolecarboxaldehyde (6.6 mg) and sodium cyanoborohydride (3.8 mg) and stirredfor additional 20 hours. The solution was added with water and thenadded with sodium bicarbonate to adjust the solution to pH 8, followedby extraction with chloroform. The organic layer was washed with asaturated aqueous sodium bicarbonate solution and dried with anhydroussodium sulfate. The residue obtained by distilling the solvent off waspurified through silica gel column chromatography (chloroform/methanol)and treated with hydrochloric acid, thereby obtaining hydrochloride(30.7 mg) of the subject compound as a pale-yellow solid.

MS(FAB, Pos.): m/z=506[M+H]⁺

¹H-NMR(500 MHz, CDCl₃): δ=0.89(6H, t, J=7.3 Hz), 1.60–1.70(8H, m),2.92–2.96(4H, m), 3.00–3.05(2H, m), 3.59(2H, t, J=6.8 Hz), 3.70(3H, s),3.92(2H, s), 4.12(2H, s), 4.20(2H, s), 7.51(1H, d, J=1.7 Hz), 7.53(1H,d, J=1.7 Hz), 7.64(2H, s), 7.75(1H, d, J=7.6 Hz), 7.83(1H, d, J=7.6 Hz),7.86(1H, s), 10.24(1H, br).

Next, the structural formulas of the respective compounds produced inProduction Examples described above are listed in Table 1.

TABLE 1 No. Structural Formula 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20 21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

The results of the activity test and the like for the compound of thepresent invention will be shown below.

Test Example 1

Immediately after infection, HIV-1_(IIIB) infected MT-4 cells(3.0×10⁴/well, MOI (Multiplicity of infection): 0.01) were added to a96-well microtiter plate together with the test compounds havingdifferent concentrations. The cells were cultured in a carbon dioxideincubator at 37° C. for 5 days, and the number of living cells wasmeasured in accordance with the MTT (tetrazolium) method (Pawels, etal., Journal of Virology Method, 20, 309–321 (1998)). The antiviralactivity is represented by the concentration required for inhibition ofcell disorder due to HIV infection by 50% (EC₅₀: 50% EffectiveConcentration) (μM), and the results are shown in Table 2.

TABLE 2 Compound No. EC50[μM] 1 0.004 2 0.003 3 0.003 11 0.023 12 0.04919 0.002 25 0.002 49 0.002 61 0.002 75 0.002 98 0.003 109 0.002 1160.002 127 0.003

Test Example 2

MT-4 cells (5×10⁶/0.2 ml/well) were cultured on a 24-well microtiterplate. After the cells were incubated for 24 hours at 37° C. in a carbondioxide gas incubator, a culture medium was replaced with a buffersolution (0.1% BSA-containing RPMI-1640). Together with a ligand¹²⁵I-SDF-1, (specific activity: 2,200 Ci/mmol; available from DaiichiPure Chemicals Co., Ltd. (Tokyo)), test materials with variousconcentrations were subjected to a binding reaction for 2 hours underice-cooling. Ligands that did not bind in cold PBS were washed out, andthen the radioactivities of bound ligands were measured with ascintillation counter (available from Japan Packard (Tokyo)). Then, arate of inhibition of the binding between radio-active ligands andreceptors CXCR4 by a test material was calculated (a binding-inhibition% at 0.1 μM).

The results are shown in Table 3.

TABLE 3 Inhibition Compound No. rate (%) 1 100.0 2 100.0 3 100.0 11 95.012 95.0 19 100.0 25 100.0 49 100.0 61 100.0 75 100.0 98 100.0 109 100.0116 100.0 127 100.0

Test Example 3

The aforementioned compound was examined for acute toxicity.Specifically, 7-week-old ICR mice (male) were divided into severalgroups (4 or 5 mice in each group), and the mice were bred for 1 weekfor habituation. Subsequently, each of the compounds of Examples wasdissolved in distilled water or physiological saline, and the solutionwas administered to the mice via tail vein (dose: 2.5 mg/kg) once. Then,dead mice were counted. The results are shown in Table 4.

As shown in Table 4, Test Example 3 confirmed that the administration ofeach compound did not cause any death and the compounds did not haveacute toxicity.

TABLE 4 Dead mice/ Compound No. test mice 1 0/5 2 0/5 3 0/5 11 0/5 120/5 19 0/5 25 0/5 49 0/5 61 0/5 75 0/5 98 0/5 109 0/5 116 0/5 127 0/5

Test Example 4

34.6% of the compound No. 86, 34.6% of lactose (Japanese Pharmacopoeia;hereinafter, referred to as “JP”), 17.3% of corn starch (JP), 7.3% ofhydroxypropylcellulose (JP), and 6.2% of low-substitutionhydroxypropylcellulose (JP) were sieved and mixed well in a plastic bag.Purified water (JP) in an amount equal to those compounds was added tothe mixture, and then a wet cake was obtained by kneading the mixturefor 20 minutes with a biaxial kneader. The wet cake was granulated usingan extrusion granulating machine (diameter of cylindrical aperture: 1mm), and then the granulated product was dried using a fluidized-beddryer (40° C., 30 minutes). The dried granules were sieved.Subsequently, magnesium stearate was added to the sieved product in theproportion of 1% of magnesium stearate to 99% of sieved product and thenthe whole was mixed well, followed by making tablets having an averageweight of 292 mg using a tableting machine.

In addition, an undercoat solution was prepared by dissolving 8% ofhydroxypropylmethylcellulose (JP) and 1.6% of macrogol 6000 (JP) inpurified water (JP) so as to be 100% in total. An under coat tablet wasprepared by: spraying the undercoat solution using a hicoater in a ratioof 5% with respect to the weight of the tablet which was previouslymade; and subjecting the sprayed tablet to drying for 20 minutes.

Furthermore, an enteric coating solution was prepared by dissolving 10%of hydroxypropylcellulose acetate succinate (Pharmaceutical excipientstandards), 3% of triethyl citrate (JP), 2% of titanium oxide (JP), and0.05% of hydroxypropylcellulose (JP) in purified water (JP) so as to be100% in total. The enteric coating solution was sprayed using a hicoaterin a ratio of 10% with respect to the tablet weight. After the spraying,the tablet was dried for 30 minutes, thereby an enteric tablet wasprepared. This enteric tablet had properties of not allowing a maincomponent to be eluted within 2 hours in first liquid (JP), and allowing80% or more of the main component to be eluted within 30 minutes insecond liquids (JP).

INDUSTRIAL APPLICABILITY

The new amine compound according to the present invention, apharmacologically acceptable salt thereof, or a prodrug thereof canprovide a new CXCR4 antagonist. The new CXCR4 antagonist of the presentinvention has a CXCR4 antagonism, and shows, based on the CXCR4antagonism, excellent effects as a therapeutic or preventive for adisease such as: a viral infectious disease such as HIV; rheumatism; orcancer metastasis.

1. A compound represented by the following general formula (1), a pharmacologically acceptable salt thereof, or a prodrug thereof:

wherein each of n₁, n₂, and n₃ is an integer of 1; each of R₁, R₂, R₃, R₄, R₅, and R₆ is independently a hydrogen atom; A₁ is imidazole; A₂ is imidazole or imidazole substituted with an alkyl group; W is a phenyl group or naphthyl group; X is CH₂; D is a group represented by -Q-Y—B, wherein: Q is NR₁₂ and R₁₂ is a hydrogen atom or an alkyl group; Y is (CH₂)m₃ and m₃ is an integer of 2 to 4; and B is N(R₂₅R₂₆), wherein each of R₂₅ and R₂₆ are independently a hydrogen atom, a C₁–C₆ alkyl group or a C₃–C₆ cycloalkyl group.
 2. A compound according to claim 1, wherein A₂ is imidazole.
 3. A compound according to claim 1, wherein A₂ is imidazole substituted with an alkyl group.
 4. A compound according to claim 1, wherein W is a phenyl group.
 5. A compound according to claim 1, wherein R₁₂ is a methyl group.
 6. A compound according to claim 1, wherein R₂₅ and R₂₆ are a C₁–C₆ alkyl group.
 7. A pharmaceutical composition, comprising as an active ingredient a compound, a pharmacologically acceptable salt thereof, or a prodrug thereof according to claim
 1. 8. A compound, a pharmacologically acceptable salt thereof, or a prodrug thereof selected from the group consisting of: N-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N′,N′-dipropylbutane-1,4-diamine, N-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N-methyl-N′,N′-dipropylbutane-1,4-diamine, N-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N′,N′-dipropylbutane-1,4-diamine, N-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N-methyl-N′,N′-dipropylbutane-1,4-diamine, and N-cyclohexyl-N′-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N′-methyl-butane-1,4-diamine.
 9. A pharmaceutical composition, comprising as an active ingredient a compound, a pharmacologically acceptable salt thereof, or a prodrug thereof according to claim
 8. 